ES2565683T3 - Kinase Inhibitor Compounds - Google Patents

Kinase Inhibitor Compounds Download PDF

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ES2565683T3
ES2565683T3 ES07838410.4T ES07838410T ES2565683T3 ES 2565683 T3 ES2565683 T3 ES 2565683T3 ES 07838410 T ES07838410 T ES 07838410T ES 2565683 T3 ES2565683 T3 ES 2565683T3
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oxo
fluoro
acid
dihydro
amide
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Congxin Liang
Shu Gao
Zhigang Li
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Tyrogenex Inc
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Xcovery Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/48—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase
    • C12Q1/485—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving transferase involving kinase

Abstract

Un compuesto de formula (III), o sal, solvato o hidrato farmaceuticos del mismo:**Fórmula** en la que Cy es una estructura ciclica que puede ser cicloalquilo o heterociclico no aromatico, cada uno opcionalmente sustituido con Z1, Z2 y Z3; R1 es H; R2 es H; R3 es fluor; cada uno de Z1, Z2 y Z3 es independientemente: (1) hidrogeno o Z6, donde Z6 es (i) alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo; (ii) un grupo (i) que esta a si mismo sustituido con uno o mas del mismo o diferentes grupos (i); o (iii) un grupo (i) o (ii) que esta sustituido con uno o mas de los siguientes grupos (2) a (13); (2) -OR o -OZ16; (3) -SH o -SZ16; (4) -C(O)2H, C(O)qZ16, -C(O)NZ17Z18, -C(O)C(O)NZ17Z18 o -O-C(O)qZ16, donde q es 1 o 2; (5) -SO3H, -S(O)qZ16 o -S(O)qNZ17Z18; (6) halo; (7) ciano; (8) nitro; (9) -Z4-NZ17Z18; (10) -Z4-N(Z18)-Z5-NZ19Z20; (11) oxo; (12) -O-C(O)-Z16; (13) dos de Z1, Z2 y Z3 cualesquiera pueden ser juntos alquileno, alquenileno, arilo, heteroarilo o heterociclo completando un anillo saturado o insaturado de 3 a 8 miembros junto con los atomos a los que estan unidos; cada uno de Z4 y Z5 es independientemente (1) un enlace sencillo; (2) -Z11-S(O)q-Z12-; (3) -Z11-C(O)-Z12-; (4) -Z11-O-Z12-; (5) -Z11-S-Z12-; (6) -Z11-O-C(O)-Z12-; o (7) -Z11-C(O)-O-Z12; cada uno de Z11 y Z12 es independientemente (1) un enlace sencillo; (2) alquileno; (3) alquenileno; o (4) alquinileno; cada Z16 es independientemente alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo, cada uno opcionalmente sustituido con uno o mas de los siguientes grupos: (2) -OH o -OZ21; (3) -SH o -SZ21; (4) -C(O)2H, C(O)qZ21, -C(O)NZ17Z18, -C(O)C(O)NZ17Z18 o -O-C(O)qZ21, donde q es 1 o 2; (5) -SO3H, -S(O)qZ21 o -S(O)qNZ17Z18; (6) halo; (7) ciano; (8) nitro; (9) -Z4-NZ17Z18; (10) -Z4-N(Z18)-Z5-NZ19Z20; (11) oxo; (12) -O-C(O)-Z21; cada Z17 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo; cada Z18 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo; cada Z19 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo; cada Z20 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo; cada Z21 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo; cada Z22 es independientemente, (2) -OH o -OZ21; (3) -SH o -SZ21; (4) -C(O)2H, C(O)qZ21, -C(O)NZ21Z21, -C(O)C(O)NZ21Z21 o -O-C(O)qZ21, donde q es 1 o 2; (5) -SO3H, -S(O)qZ21 o -S(O)qNZ21Z21; (6) halo; (7) ciano; (8) nitro; (9) -Z4-NZ21Z21; (10) -Z4-N(Z21)-Z5-NZ21Z21; (11) oxo; (12) -O-C(O)-Z21; donde Z17 y Z18, o Z19 y Z20, junto con el atomo de nitrogeno al que estan unidos pueden ser un heterociclo que esta sin sustituir o sustituido con 1, 2 o 3 Z22 independientes; y donde dos de Z18, Z19 o Z20 cualesquiera, junto con los atomos de nitrogeno a los que estan unidos pueden ser un anillo saturado o insaturado mono, bi o tri-heterociclico de 3 a 12 miembros que esta sin sustituir o sustituido con 1, 2 o 3 Z22 independientes.A compound of formula (III), or pharmaceutical salt, solvate or hydrate thereof: ** Formula ** in which Cy is a cyclic structure which can be cycloalkyl or non-aromatic heterocyclic, each optionally substituted with Z1, Z2 and Z3 ; R1 is H; R2 is H; R3 is fluorine; each of Z1, Z2 and Z3 is independently: (1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; (ii) a group (i) that is itself substituted with one or more of the same or different groups (i); or (iii) a group (i) or (ii) that is substituted with one or more of the following groups (2) to (13); (2) -OR or -OZ16; (3) -SH or -SZ16; (4) -C (O) 2H, C (O) qZ16, -C (O) NZ17Z18, -C (O) C (O) NZ17Z18 or -O-C (O) qZ16, where q is 1 or 2; (5) -SO3H, -S (O) qZ16 or -S (O) qNZ17Z18; (6) halo; (7) cyano; (8) nitro; (9) -Z4-NZ17Z18; (10) -Z4-N (Z18) -Z5-NZ19Z20; (11) oxo; (12) -O-C (O) -Z16; (13) two of any Z1, Z2 and Z3 may together be alkylene, alkenylene, aryl, heteroaryl or heterocycle by completing a saturated or unsaturated ring of 3 to 8 members together with the atoms to which they are attached; each of Z4 and Z5 is independently (1) a single link; (2) -Z11-S (O) q-Z12-; (3) -Z11-C (O) -Z12-; (4) -Z11-O-Z12-; (5) -Z11-S-Z12-; (6) -Z11-O-C (O) -Z12-; or (7) -Z11-C (O) -O-Z12; each of Z11 and Z12 is independently (1) a single link; (2) alkylene; (3) alkenylene; or (4) alkynylene; Each Z16 is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl, each optionally substituted with one or more of the following groups: -OH or -OZ21; (3) -SH or -SZ21; (4) -C (O) 2H, C (O) qZ21, -C (O) NZ17Z18, -C (O) C (O) NZ17Z18 or -O-C (O) qZ21, where q is 1 or 2; (5) -SO3H, -S (O) qZ21 or -S (O) qNZ17Z18; (6) halo; (7) cyano; (8) nitro; (9) -Z4-NZ17Z18; (10) -Z4-N (Z18) -Z5-NZ19Z20; (11) oxo; (12) -O-C (O) -Z21; Each Z17 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; each Z18 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; each Z19 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; Each Z20 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; Each Z21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; each Z22 is independently, (2) -OH or -OZ21; (3) -SH or -SZ21; (4) -C (O) 2H, C (O) qZ21, -C (O) NZ21Z21, -C (O) C (O) NZ21Z21 or -O-C (O) qZ21, where q is 1 or 2; (5) -SO3H, -S (O) qZ21 or -S (O) qNZ21Z21; (6) halo; (7) cyano; (8) nitro; (9) -Z4-NZ21Z21; (10) -Z4-N (Z21) -Z5-NZ21Z21; (11) oxo; (12) -O-C (O) -Z21; where Z17 and Z18, or Z19 and Z20, together with the nitrogen atom to which they are attached can be a heterocycle that is unsubstituted or substituted with 1, 2 or 3 independent Z22; and where two of any Z18, Z19 or Z20, together with the nitrogen atoms to which they are attached, can be a mono, bi or tri-heterocyclic saturated or unsaturated ring of 3 to 12 members that is unsubstituted or substituted with 1, 2 or 3 independent Z22.

Description

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DESCRIPCIONDESCRIPTION

Compuestos inhibidores de quinasa AntecedentesKinase Inhibitor Compounds Background

Sunitinib es un potente inhibidor de quinasa multi-diana que es eficaz en el tratamiento de canceres, de forma mas notable carcinoma de celulas renales y tumor de estroma GI aprobado por FDA. Tambien esta experimentando ensayos clmicos en otros varios canceres. Su estructura es un derivado indolinona caracterizado por una cadena lateral dietilaminoetilo basica. Aunque Sunitinib es muy eficaz, su aplicacion esta impedida por los efectos secundarios. La toxicidad mas comun y grave en clinica es neutropenia y fatiga.Sunitinib is a potent multi-target kinase inhibitor that is effective in the treatment of cancers, most notably renal cell carcinoma and GI stromal tumor approved by the FDA. He is also experiencing clinical trials in several other cancers. Its structure is an indolinone derivative characterized by a basic diethylaminoethyl side chain. Although Sunitinib is very effective, its application is hindered by side effects. The most common and serious toxicity in the clinic is neutropenia and fatigue.

imagen1image 1

El documento WO 02/096361 describe derivados de 5-aralquilsulfonil-3-(pirrol-2-ilmetiliden)-2-indolinona que son inhibidores de quinasa y por lo tanto adecuados para tratamiento de enfermedades mediadas por actividad anormal de proteina quinasa tal como cancer. Los documentos WO 2006/052936, WO 2008/033743 y WO 02/02551 describen compuestos de indolinona sustituidos que tambien son adecuados para el tratamiento de enfermedades mediadas por actividad proteina quinasa anormal.WO 02/096361 describes derivatives of 5-aralkylsulfonyl-3- (pyrrol-2-ylmethyliden) -2-indolinone which are kinase inhibitors and therefore suitable for treatment of diseases mediated by abnormal protein kinase activity such as cancer . WO 2006/052936, WO 2008/033743 and WO 02/02551 describe substituted indolinone compounds that are also suitable for the treatment of diseases mediated by abnormal protein kinase activity.

Esta invencion describe una nueva clase de derivados de Sunitinib con una cadena lateral ciclica que reemplaza la cadena lateral dietilaminoetilo de Sunitinib. Estan disenados para superar el problema de fatiga de Sunitinib mejorando su selectividad. Recientemente, un estudio proteomico de un analogo de Sunitinib, SU6668 descubrio que SU6668 inhibe, entre otras proteinas, AMPK (Godl et al, Cancer Res 2005, 65, 6919). Como AMPK es un detector clave del estado de potencia y energia en musculo esqueletico (vease la revision de Hardie y Sakamoto, Physiology 2006, 21,48-60), se hipotetizo que la inhibicion de AMPK podria ser la causa de la fatiga por toxicidad observada clinicamente de Sunitinib.This invention describes a new class of Sunitinib derivatives with a cyclic side chain that replaces the Sunitinib diethylaminoethyl side chain. They are designed to overcome Sunitinib's fatigue problem by improving its selectivity. Recently, a proteomical study of a Sunitinib analogue, SU6668 discovered that SU6668 inhibits, among other proteins, AMPK (Godl et al, Cancer Res 2005, 65, 6919). As AMPK is a key detector of the state of power and energy in skeletal muscle (see the review of Hardie and Sakamoto, Physiology 2006, 21,48-60), it was hypothesized that the inhibition of AMPK could be the cause of fatigue due to toxicity clinically observed from Sunitinib.

Por tanto, los derivados ciclicos de Sunitinib estan disenados para reducir la actividad inhibidora de AMPK, aliviando de ese modo el problema de fatiga de Sunitinib.Therefore, Sunitinib cyclic derivatives are designed to reduce AMPK inhibitory activity, thereby alleviating Sunitinib's fatigue problem.

SumarioSummary

La invencion se refiere a compuestos heterociclicos, composiciones que comprenden los compuestos, y metodos para usar los compuestos y composiciones de compuestos. Los compuestos y composiciones que los comprenden son utiles para tratar enfermedades o sintomas de enfermedades, incluyendo los mediados o asociados con enzimas quinasa.The invention relates to heterocyclic compounds, compositions comprising the compounds, and methods for using the compounds and compound compositions. The compounds and compositions comprising them are useful for treating diseases or symptoms of diseases, including those mediated or associated with kinase enzymes.

Un aspecto es un compuesto de formula (III), o una sal, un solvato o un hidrato farmaceuticos del mismo:One aspect is a compound of formula (III), or a pharmaceutical salt, solvate or hydrate thereof:

imagen2image2

en la que Cy es una estructura ciclica que puede ser cicloalquilo o heterociclico no aromatico, cada uno opcionalmente sustituido con Zi, Z2 y Z3;wherein Cy is a cyclic structure that can be non-aromatic cycloalkyl or heterocyclic, each optionally substituted with Zi, Z2 and Z3;

Ri es H;Ri is H;

R2 es H;R2 is H;

R3 es fluor;R3 is fluorine;

cada uno de Zi, Z2 y Z3 es independientemente:Each of Zi, Z2 and Z3 is independently:

(1) hidrogeno o Z6, donde Z6 es (i) alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo; (ii) un grupo (i) que esta sustituido por uno o mas del mismo o diferentes grupos (i); o (iii)(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; (ii) a group (i) that is substituted by one or more of the same or different groups (i); or (iii)

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un grupo (i) o (ii) que esta sustituido con uno o mas de los siguientes grupos (2) a (13);a group (i) or (ii) that is substituted with one or more of the following groups (2) to (13);

(2) -OH o -OZis;(2) -OH or -OZis;

(3) -SH o -SZie;(3) -SH or -SZie;

(4) -C(O)2H, C(O)qZie, -C(O)NZi7Zi8, -C(O)C(O)NZi7Zi8 o -O-C(O)qZie, donde q es 1 o 2;(4) -C (O) 2H, C (O) qZie, -C (O) NZi7Zi8, -C (O) C (O) NZi7Zi8 or -O-C (O) qZie, where q is 1 or 2;

(5) -SO3H, -S(O)qZie o -S(O)qNZi7Zi8;(5) -SO3H, -S (O) qZie or -S (O) qNZi7Zi8;

(6) halo;(6) halo;

(7) ciano;(7) cyano;

(8) nitro;(8) nitro;

(9) -Z4-NZ17Z18;(9) -Z4-NZ17Z18;

(10) -Z4-N(Zi8)-Z5-NZi9Z2o;(10) -Z4-N (Zi8) -Z5-NZi9Z2o;

(11) oxo;(11) oxo;

(12) -O-C(O)-Zie;(12) -O-C (O) -Zie;

(13) cualesquiera dos de Zi, Z2 y Z3 pueden ser juntos alquileno, alquenileno, arilo, heteroarilo o heterociclo completando un anillo saturado o insaturado de 3 a 8 miembros junto con los atomos a los que estan unidos;(13) any two of Zi, Z2 and Z3 may together be alkylene, alkenylene, aryl, heteroaryl or heterocycle by completing a saturated or unsaturated ring of 3 to 8 members together with the atoms to which they are attached;

cada uno de Z4 y Z5 es independientementeeach of Z4 and Z5 is independently

(1) un enlace sencillo;(1) a simple link;

(2) -Zii-S(O)q-Zi2-;(2) -Zii-S (O) q-Zi2-;

(3) -Zii-C(O)-Zi2-;(3) -Zii-C (O) -Zi2-;

(4) -Z11-O-Z12-;(4) -Z11-O-Z12-;

(5) -Z11-S-Z12-;(5) -Z11-S-Z12-;

(6) -Zii-O-C(O)-Zi2-; o(6) -Zii-O-C (O) -Zi2-; or

(7) -Zii-C(O)-O-Zi2;(7) -Zii-C (O) -O-Zi2;

cada uno de Zii y Z12 es independientementeeach of Zii and Z12 is independently

(1) un enlace sencillo;(1) a simple link;

(2) alquileno;(2) alkylene;

(3) alquenileno; o(3) alkenylene; or

(4) alquinileno;(4) alkynylene;

cada Zie es independientemente alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo, cada uno opcionalmente sustituido con uno o mas de los siguientes grupos:Each Zie is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl, each optionally substituted with one or more of the following groups:

(2) -OH o -OZ21;(2) -OH or -OZ21;

(3) -SH o -SZ21;(3) -SH or -SZ21;

(4) -C(O)2H, C(O)qZ2i, -C(O)NZi7Zi8, -C(O)C(O)NZi7Zi8 o -O-C(O)qZ2i, donde q es 1 o 2;(4) -C (O) 2H, C (O) qZ2i, -C (O) NZi7Zi8, -C (O) C (O) NZi7Zi8 or -O-C (O) qZ2i, where q is 1 or 2;

(5) -SO3H, -S(O)qZ2i o -S(O)qNZl7Zl8;(5) -SO3H, -S (O) qZ2i or -S (O) qNZl7Zl8;

(6) halo;(6) halo;

(7) ciano;(7) cyano;

(8) nitro;(8) nitro;

(9) -Z4-NZ17Z18;(9) -Z4-NZ17Z18;

(10) -Z4-N(Zi8) -Z5-NZ19Z20;(10) -Z4-N (Zi8) -Z5-NZ19Z20;

(11) oxo;(11) oxo;

(12) -O-C(O)-Z2i;(12) -O-C (O) -Z2i;

cada Z17 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Z17 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl,

heterociclo o heterocicloalquilo;heterocycle or heterocycloalkyl;

cada Zi8 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Zi8 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl,

heterociclo o heterocicloalquilo;heterocycle or heterocycloalkyl;

cada Z19 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Z19 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl,

heterociclo o heterocicloalquilo;heterocycle or heterocycloalkyl;

cada Z20 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Z20 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl,

heterociclo o heterocicloalquilo;heterocycle or heterocycloalkyl;

cada Z21 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Z21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,

cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl,

heterociclo o heterocicloalquilo; cada Z22 es independientemente,heterocycle or heterocycloalkyl; Each Z22 is independently,

(2) -OH o -OZ21;(2) -OH or -OZ21;

(3) -SH o -SZ21;(3) -SH or -SZ21;

(4) -C(O)2H, C(O)qZ2i, -C(O)NZ2iZ2i, -C(O)C(O)NZ2iZ2i o -O-C(O)qZ2i, donde q es 1 o 2;(4) -C (O) 2H, C (O) qZ2i, -C (O) NZ2iZ2i, -C (O) C (O) NZ2iZ2i or -O-C (O) qZ2i, where q is 1 or 2;

(5) -SO3H, -S(O)qZ2i o -S(O)qNZ2lZ2i;(5) -SO3H, -S (O) qZ2i or -S (O) qNZ2lZ2i;

(6) halo;(6) halo;

(7) ciano;(7) cyano;

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(8) nitro;(8) nitro;

(9) -Z4-NZ21Z21;(9) -Z4-NZ21Z21;

(10) -Z4-N(Z2i)-Z5-NZ2iZ21;(10) -Z4-N (Z2i) -Z5-NZ2iZ21;

(11) oxo;(11) oxo;

(12) -O-C(O)-Z2i;(12) -O-C (O) -Z2i;

donde Z17 y Zi8, o Z19 y Z20, junto con el atomo de nitrogeno al que estan unidos pueden ser un heterociclo que esta sin sustituir o sustituido con 1,2 o 3 Z22 independientes; ywhere Z17 and Zi8, or Z19 and Z20, together with the nitrogen atom to which they are attached can be a heterocycle that is unsubstituted or substituted with 1,2 or 3 independent Z22; Y

donde cualesquiera dos de Zi8, Z19 o Z20 junto con los atomos de nitrogeno a los que estan unidos pueden ser un anillo saturado o insaturado mono, bi o triheterodclico de 3 a 12 miembros que esta sin sustituir o sustituido con 1,2 o 3 Z22 independientes.where any two of Zi8, Z19 or Z20 together with the nitrogen atoms to which they are attached can be a mono, bi or tri-heterocyclic saturated or unsaturated ring of 3 to 12 members that is unsubstituted or substituted with 1,2 or 3 Z22 independent.

En otros aspectos, los compuestos son aquellos de cualquiera de las formulas en el presente documento (incluyendo cualquier combinacion de los mismos):In other aspects, the compounds are those of any of the formulas herein (including any combination thereof):

en las que Cy esta opcionalmente sustituido cicloalquilo;in which Cy is optionally substituted cycloalkyl;

en las que Cy es un anillo heterociclico opcionalmente sustituido de 5 miembros; en las que Cy es un anillo heterociclico opcionalmente sustituido de 6 miembros;wherein Cy is an optionally substituted 5-membered heterocyclic ring; wherein Cy is an optionally substituted 6-membered heterocyclic ring;

en las que el compuesto de formula III es un compuesto definido en cualquiera de las tablas en el presente documento, o una sal, solvato o hidrato farmaceuticos del mismo.wherein the compound of formula III is a compound defined in any of the tables herein, or a pharmaceutical salt, solvate or hydrate thereof.

En otro aspecto, la invencion se refiere a un compuesto de la invencion para su uso en un metodo para tratar una enfermedad o sintoma de enfermedad en un sujeto que lo necesite, que incluye administrar al sujeto una cantidad eficaz de un compuesto de cualquier formula de este documento, o sal farmaceutica, solvato o hidrato del mismo (o composition del mismo). La enfermedad o sintoma de enfermedad puede ser cualquiera de los modulados por una enzima quinasa (por ejemplo, VEGFR, PDGFR, KIT, Flt-3, RET). La enfermedad o sintoma de enfermedad puede ser cancer, incluyendo, por ejemplo, carcinoma de celulas renales y tumor de estroma GI, tumor o trastorno proliferativo.In another aspect, the invention relates to a compound of the invention for use in a method for treating a disease or disease symptom in a subject in need thereof, which includes administering to the subject an effective amount of a compound of any formula of this document, or pharmaceutical salt, solvate or hydrate thereof (or composition thereof). The disease or disease symptom can be any of those modulated by an enzyme kinase (for example, VEGFR, PDGFR, KIT, Flt-3, RET). The disease or disease symptom may be cancer, including, for example, renal cell carcinoma and GI stromal tumor, tumor or proliferative disorder.

En otro aspecto, la invencion se refiere a un compuesto de la invencion para su uso en un metodo para modular (por ejemplo, inhibir, antagonizar, agonizar) la actividad quinasa, que incluye poner en contacto una quinasa con un compuesto de cualquiera de las formulas de este documento o sal, solvato o hidrato farmaceutico del mismo (o composicion del mismo).In another aspect, the invention relates to a compound of the invention for use in a method of modulating (for example, inhibiting, antagonizing, agonizing) kinase activity, which includes contacting a kinase with a compound of any of the formulas of this document or salt, solvate or pharmaceutical hydrate thereof (or composition thereof).

En otro aspecto, la invencion se refiere a un compuesto de la invencion para su uso en un metodo para preparar un compuesto de formula III de este documento, que incluye hacer reaccionar un intermedio definido en este documento con un reactivo para proporcionar un compuesto de formula III como se define en este documento.In another aspect, the invention relates to a compound of the invention for use in a method for preparing a compound of formula III of this document, which includes reacting an intermediate defined herein with a reagent to provide a compound of formula III as defined in this document.

En otro aspecto, la invencion se refiere a una composicion que incluye un compuesto de cualquiera de las formulas de este documento, o sal, solvato o hidrato farmaceuticamente aceptable del mismo, y un vehiculo farmaceuticamente aceptable. La composicion puede incluir adicionalmente un agente terapeutico adicional.In another aspect, the invention relates to a composition that includes a compound of any of the formulas herein, or pharmaceutically acceptable salt, solvate or hydrate thereof, and a pharmaceutically acceptable carrier. The composition may additionally include an additional therapeutic agent.

En otro aspecto, la invencion se refiere a un metodo para modular la actividad de un receptor de factor de crecimiento (por ejemplo, VEGFR, PDGFR, KIT, Flt-3, RET) en un sujeto que lo necesita, que incluye administrar al sujeto una cantidad eficaz de un compuesto de cualquiera de las formulas de este documento, o sal farmaceutica del mismo (o composicion del mismo).In another aspect, the invention relates to a method for modulating the activity of a growth factor receptor (eg, VEGFR, PDGFR, KIT, Flt-3, RET) in a subject in need thereof, which includes administering to the subject. an effective amount of a compound of any of the formulas herein, or pharmaceutical salt thereof (or composition thereof).

En otros aspectos, la invencion se refiere a una composicion que comprende un compuesto de cualquiera de las formulas de este documento, un agente terapeutico adicional, y un vehiculo farmaceuticamente aceptable. El agente terapeutico adicional puede ser un agente antineoplasico, agente antitumoral, agente antiproliferativo, o cualquier otro agente normalmente administrado como agente principal o adyuvante en protocolos de tratamiento del cancer (por ejemplo, antiemeticos, antianemia, etc.).In other aspects, the invention relates to a composition comprising a compound of any of the formulas herein, an additional therapeutic agent, and a pharmaceutically acceptable carrier. The additional therapeutic agent may be an antineoplastic agent, antitumor agent, antiproliferative agent, or any other agent normally administered as a principal or adjuvant agent in cancer treatment protocols (eg, antiemetics, antianemia, etc.).

Otro aspecto mas de este invencion se refiere a un compuesto de la invencion para su uso en un metodo para tratar a un sujeto (por ejemplo, mamifero, ser humano, caballo, perro, gato) que tiene una enfermedad o sintoma de enfermedad (incluyendo, aunque sin limitation) que es o esta asociado con cancer, uno o mas tumores, trastornos proliferativos, etc. el metodo incluye administrar al sujeto (incluyendo un sujeto identificado con necesidad de dicho tratamiento) una cantidad eficaz de un compuesto descrito en este documento, o una composicion descrita en este documento para producir dicho efecto. La identification de un sujeto que necesite dicho tratamiento puede ser a juicio de un sujeto o un profesional de asistencia sanitaria y puede ser subjetivo (por ejemplo, opinion) u objetivo (por ejemplo, medible por un ensayo o metodo de diagnostico).Another aspect of this invention relates to a compound of the invention for use in a method of treating a subject (e.g., mammal, human, horse, dog, cat) that has a disease or disease symptom (including , although without limitation) which is or is associated with cancer, one or more tumors, proliferative disorders, etc. The method includes administering to the subject (including a subject identified in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce said effect. The identification of a subject that needs such treatment can be in the opinion of a subject or a healthcare professional and can be subjective (for example, opinion) or objective (for example, measurable by a diagnostic test or method).

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Otro aspecto mas de esta invencion se refiere a un compuesto de la invencion para su uso en un metodo para tratar a un sujeto (por ejemplo, mam^fero, ser humano, caballo, perro, gato) que tiene una enfermedad o sintoma de enfermedad mediada por quinasa (incluyendo, aunque sin limitacion, cancer, tumor, trastorno proliferativo, etc.). El metodo incluye administrar al sujeto (incluyendo un sujeto identificado con necesidad de dicho tratamiento) una cantidad eficaz de un compuesto descrito en este documento, o una composicion descrita en este documento para producir dicho efecto. La identificacion de un sujeto que necesite dicho tratamiento puede ser a juicio de un sujeto o un profesional de asistencia sanitaria y puede ser subjetivo (por ejemplo, opinion) u objetivo (por ejemplo, medible por un ensayo o metodo de diagnostico).Yet another aspect of this invention relates to a compound of the invention for use in a method of treating a subject (eg, mammal, human being, horse, dog, cat) that has a disease or disease symptom. kinase mediated (including, but not limited to, cancer, tumor, proliferative disorder, etc.). The method includes administering to the subject (including a subject identified in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce said effect. The identification of a subject that needs such treatment can be in the opinion of a subject or a healthcare professional and can be subjective (for example, opinion) or objective (for example, measurable by a diagnostic test or method).

Los metodos de tratamiento incluyen aspectos donde los efectos secundarios adversos estan minimizados o son inexistentes. En un aspecto, el compuesto inhibe selectivamente una diana de quinasa, preferentemente sobre la inhibicion de AMPK; en otro aspecto, el compuesto inhibe selectivamente una diana de quinasa preferentemente sobre la inhibicion de AMPK con mayor selectividad que Sunitinib; en otro aspecto, el sujeto experimenta poco o ningun efecto secundario de fatiga.Treatment methods include aspects where adverse side effects are minimized or non-existent. In one aspect, the compound selectively inhibits a kinase target, preferably upon AMPK inhibition; in another aspect, the compound selectively inhibits a kinase target preferably on AMPK inhibition with greater selectivity than Sunitinib; In another aspect, the subject experiences little or no side effects of fatigue.

Otro aspecto, es un compuesto de la invencion para su uso en un metodo para identificar un inhibidor de quinasa que inhiba selectivamente una diana de quinasa preferentemente sobre la inhibicion de AMPK, que comprende; (i) evaluar un compuesto de ensayo para la inhibicion de una enzima quinasa; (ii) evaluar el compuesto de ensayo para la inhibicion de AMPK; (iii) evaluar si el compuesto de ensayo inhibe una diana de quinasa preferentemente sobre la inhibicion de AMPK. Otros aspectos son el metodo donde el compuesto de ensayo inhibe una diana de quinasa preferentemente sobre la inhibicion de AMPK con mayor selectividad que Sunitinib.Another aspect is a compound of the invention for use in a method for identifying a kinase inhibitor that selectively inhibits a kinase target preferably on AMPK inhibition, which comprises; (i) evaluate a test compound for the inhibition of an enzyme kinase; (ii) evaluate the test compound for AMPK inhibition; (iii) evaluate whether the test compound inhibits a kinase target preferably on AMPK inhibition. Other aspects are the method where the test compound inhibits a kinase target preferably on the inhibition of AMPK with greater selectivity than Sunitinib.

Otro aspecto es un compuesto de la invencion para su uso en un metodo para tratar una enfermedad o sintoma de enfermedad en un sujeto que lo necesite, que comprende administrar al sujeto una cantidad eficaz de un compuesto identificado por el metodo anterior, o sal, solvato o hidrato farmaceutico del mismo.Another aspect is a compound of the invention for use in a method for treating a disease or disease symptom in a subject in need thereof, which comprises administering to the subject an effective amount of a compound identified by the above method, or salt, solvate. or pharmaceutical hydrate thereof.

La invencion tambien se refiere a un metodo para preparar un compuesto descrito en este documento, incluyendo el metodo cualquier reaccion o reactivo definido en los esquemas o ejemplos de este documento. Como alternativa, el metodo incluye tomar uno cualquiera de los compuestos intermedios descritos en este documento y hacerlo reaccionar con uno o mas reactivos quimicos en una o mas etapas para producir un compuesto descrito en este documento.The invention also relates to a method for preparing a compound described herein, the method including any reaction or reagent defined in the schemes or examples herein. Alternatively, the method includes taking any one of the intermediate compounds described herein and reacting it with one or more chemical reagents in one or more steps to produce a compound described herein.

Tambien dentro del alcance de esta invencion esta un producto envasado. El producto envasado incluye un recipiente, uno de los compuestos mencionados anteriormente en el recipiente, y una leyenda (por ejemplo, una etiqueta o un prospecto) asociado con el recipiente y que indique la administracion del compuesto para tratar un trastorno asociado con modulacion de quinasa (por ejemplo, cancer, tumor, trastorno proliferativo, etc.).Also within the scope of this invention is a packaged product. The packaged product includes a container, one of the compounds mentioned above in the container, and a legend (for example, a label or a leaflet) associated with the container and indicating the administration of the compound to treat a disorder associated with kinase modulation (for example, cancer, tumor, proliferative disorder, etc.).

Otro aspecto de la invencion es un compuesto de la invencion para su uso en el tratamiento o prevencion en un sujeto de una enfermedad, trastorno o sintoma del mismo definido en este documento.Another aspect of the invention is a compound of the invention for use in the treatment or prevention in a subject of a disease, disorder or symptom thereof defined herein.

Otro aspecto de la invencion es el uso de un compuesto de la invencion en la fabrication de un medicamento para el tratamiento o prevencion en un sujeto de una enfermedad, trastorno o sintoma del mismo definido en este documento.Another aspect of the invention is the use of a compound of the invention in the manufacture of a medicament for the treatment or prevention in a subject of a disease, disorder or symptom thereof defined herein.

En otras realizaciones, los compuestos, composiciones, y metodos definidos en este documento son cualquiera de los compuestos de las tablas de este documento o metodos que los incluyen.In other embodiments, the compounds, compositions, and methods defined herein are any of the compounds in the tables of this document or methods that include them.

Los detalles de una o mas realizaciones de la invencion se exponen en lo dibujos adjuntos y la siguiente description. Otras caracteristicas, objetivos, y ventajas de la invencion seran evidentes a partir de la descripcion y a partir de las reivindicaciones.The details of one or more embodiments of the invention are set forth in the accompanying drawings and the following description. Other features, objectives, and advantages of the invention will be apparent from the description and from the claims.

Descripcion detalladaDetailed description

Como se usa en el presente documento, el termino "halo" o "halogeno" se refiere a cualquier radical de fluor, cloro, bromo o yodo.As used herein, the term "halo" or "halogen" refers to any radical of fluorine, chlorine, bromine or iodine.

Las expresiones "alq" o "alquilo" se refieren a grupos hidrocarburo de cadena lineal o ramificada que tienen de 1 a 12 atomos de carbono, preferiblemente de 1 a 8 atomos de carbono. La expresion "alquilo inferior" se refiere a grupos alquilo de 1 a 4 atomos de carbono (inclusive). El termino "arilalquilo" se refiere a un resto en el que un atomo de alquil hidrogeno se reemplaza por un grupo arilo. El termino "alquenilo" se refiere a grupos hidrocarburo de cadena lineal o ramificada de 2 a 10, preferiblemente de 2 a 4, atomos de carbono que tienen al menos un doble enlace. Cuando un grupo alquenilo esta unido a un atomo de nitrogeno, se prefiere que tal grupo no este unido directamente a traves de un carbono que tenga un doble enlace.The terms "alq" or "alkyl" refer to straight or branched chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1 to 8 carbon atoms. The term "lower alkyl" refers to alkyl groups of 1 to 4 carbon atoms (inclusive). The term "arylalkyl" refers to a moiety in which an alkyl hydrogen atom is replaced by an aryl group. The term "alkenyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one double bond. When an alkenyl group is attached to a nitrogen atom, it is preferred that such a group is not directly linked through a carbon having a double bond.

El termino "alcoxi" se refiere a un radical -O-alquilo. El termino "alquilendioxo" se refiere a una especie divalente de la estructura -O-R-O-, en la que R representa un alquileno.The term "alkoxy" refers to a radical -O-alkyl. The term "alkylenedioxo" refers to a divalent species of the structure -O-R-O-, in which R represents an alkylene.

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El termino "alquinilo" se refiere a grupos hidrocarburo de cadena lineal o ramificada de 2 a 10, preferiblemente de 2 a 4, atomos de carbono que tienen al menos un triple enlace. Cuando un grupo alquinilo esta unido a un atomo de nitrogeno, se prefiere que tal grupo no este unido directamente a traves de un carbono que tenga un triple enlace.The term "alkynyl" refers to straight or branched chain hydrocarbon groups of 2 to 10, preferably 2 to 4, carbon atoms having at least one triple bond. When an alkynyl group is attached to a nitrogen atom, it is preferred that such a group is not directly linked through a carbon having a triple bond.

El termino "alquileno" se refiere a un puente de cadena lineal divalente de 1 a 5 atomos de carbono conectado por enlaces sencillos (por ejemplo, -(CH2)x-, en la que x es de 1 a 5), que puede estar sustituido con 1 a 3 grupos alquilo inferior.The term "alkylene" refers to a divalent linear chain bridge of 1 to 5 carbon atoms connected by single bonds (for example, - (CH2) x-, in which x is 1 to 5), which may be substituted with 1 to 3 lower alkyl groups.

El termino "alquenileno" se refiere a un puente de cadena lineal de 2 a 5 atomos de carbono que tiene uno o dos dobles enlaces que esta conectado por enlaces sencillos y pueden estar sustituido con 1 a 3 grupos alquilo inferior. Los grupos alquenileno ejemplares son - CH=CH-CH=CH-, -CH2-CH=CH-, -CH2-CH=CH-CH2-, -C(CH3)2CH=CH- y - CH(C2H5)-CH=CH-.The term "alkenylene" refers to a linear chain bridge of 2 to 5 carbon atoms that has one or two double bonds that is connected by single bonds and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkenylene groups are - CH = CH-CH = CH-, -CH2-CH = CH-, -CH2-CH = CH-CH2-, -C (CH3) 2CH = CH- and - CH (C2H5) -CH = CH-.

El termino "alquinileno" se refiere a un puente de cadena lineal de 2 a 5 atomos de carbono que tiene un triple enlace en el mismo, esta conectado por enlaces sencillos, y puede estar sustituido con 1 a 3 grupos alquilo inferior. Los grupos alquinileno ejemplares son -CC-, -CH2-CC-,-CH(CH3)-CC- y -CC-CH(C2H5)CH2-.The term "alkynylene" refers to a linear chain bridge of 2 to 5 carbon atoms that has a triple bond therein, is connected by single bonds, and may be substituted with 1 to 3 lower alkyl groups. Exemplary alkynylene groups are -CC-, -CH2-CC -, - CH (CH3) -CC- and -CC-CH (C2H5) CH2-.

Las expresiones "cicloalquilo" y "cicloalquenilo" como se emplean en el presente documento incluyen grupos hidrocarburo saturados y parcialmente insaturados dclicos, respectivamente, que tienen de 3 a 12 carbonos, preferiblemente de 3 a 8 carbonos, y mas preferiblemente de 3 a 6 carbonos.The terms "cycloalkyl" and "cycloalkenyl" as used herein include saturated and partially unsaturated hydrocarbon groups, respectively, having 3 to 12 carbons, preferably 3 to 8 carbons, and more preferably 3 to 6 carbons .

Las expresiones "Ar" o "arilo" se refieren a grupos dclicos aromaticos (por ejemplo sistemas anulares monodclicos de 6 miembros, bidclicos de 10 miembros, o tridclicos de 14 miembros) que contienen de 6 a 14 atomos de carbono. Los grupos arilo ejemplares incluyen fenilo, naftilo, bifenilo y antraceno.The terms "Ar" or "aryl" refer to aromatic cyclic groups (for example 6-membered, 10-membered, or 14-membered tricyclic ring systems) containing 6 to 14 carbon atoms. Exemplary aryl groups include phenyl, naphthyl, biphenyl and anthracene.

Las expresiones "heterociclo", "heterodclico" o "heterociclo" se refieren a grupos dclicos completamente saturados o parcialmente insaturados, por ejemplo, sistemas anulares monodclicos de 3 a 7 miembros, bidclicos de 7 a 12 miembros, o tridclicos de 10 a 15 miembros, que tienen al menos un heteroatomo en al menos un anillo, en los que 0, 1, 2 o 3 atomos de cada anillo pueden estar sustituidos por un sustituyente. Cada anillo del grupo heterodclico que contiene un heteroatomo puede tener 1, 2, 3 o 4 heteroatomos seleccionados entre atomos de nitrogeno, atomos de oxigeno y/o atomos de azufre, donde los heteroatomos de nitrogeno y azufre pueden oxidarse opcionalmente y los heteroatomos de nitrogeno pueden cuaternizarse opcionalmente. El grupo heterodclico puede estar unido a cualquier heteroatomo o atomo de carbono del anillo o el sistema anular.The terms "heterocycle", "heterodclico" or "heterocycle" refer to fully saturated or partially unsaturated cyclic groups, for example, 3 to 7-membered mono-ring, 7 to 12-membered, or 10 to 15-member tricyclic ring systems. , which have at least one heteroatom in at least one ring, in which 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Each heterodyl group ring containing a heteroatom may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where nitrogen and sulfur heteroatoms can optionally be oxidized and nitrogen heteroatoms can optionally quaternize. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or annular system.

"Heteroarilo" se refiere a un grupo anular monodclico o condensado (es decir, anillos que comparten un par adyacente de atomos) de 5 a 12 atomos en el anillo que contiene uno, dos, tres o cuatro heteroatomos en el anillo seleccionados entre N, O o S, siendo los atomos en el anillo restantes C, y, ademas, que tiene un sistema pi electrones conjugados completamente, en el que 0, 1, 2, 3 o 4 atomos de cada anillo pueden estar sustituidos por un sustituyente. Los ejemplos, sin limitacion, de grupos heteroarilo son pirrol, furano, tiofeno, imidazol, oxazol, tiazol, pirazol, piridina, pirimidina, quinolina, quinazolina, isoquinolina, purina y carbazol."Heteroaryl" refers to a monodyl or condensed ring group (ie rings that share an adjacent pair of atoms) of 5 to 12 atoms in the ring containing one, two, three or four ring heteroatoms selected from N, O or S, the remaining atoms in the ring being C, and also having a completely conjugated pi electron system, in which 0, 1, 2, 3 or 4 atoms of each ring can be substituted by a substituent. Examples, without limitation, of heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazol, thiazole, pyrazole, pyridine, pyrimidine, quinoline, quinazoline, isoquinoline, purine and carbazole.

El termino "oxo" se refiere a un atomo de oxigeno, que forma un carbonilo cuando se une a carbono, un N-oxido cuando se une a nitrogeno, y un sulfoxido o sulfona cuando se une a azufre.The term "oxo" refers to an oxygen atom, which forms a carbonyl when bonded to carbon, an N-oxide when bonded to nitrogen, and a sulfoxide or sulfone when bonded to sulfur.

El termino "acilo" se refiere a un sustituyente alquilcarbonilo, cicloalquilcarbonilo, arilcarbonilo, heterociclilcarbonilo o heteroarilcarbonilo, cualquiera de los cuales puede estar sustituido adicionalmente por sustituyentes.The term "acyl" refers to an alkylcarbonyl, cycloalkylcarbonyl, arylcarbonyl, heterocyclylcarbonyl or heteroarylcarbonyl substituent, any of which may be further substituted by substituents.

El termino "sustituyentes" se refiere a un grupo "sustituido" en cualquier grupo funcional descrito en el presente documento, por ejemplo, un grupo alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquenilo, arilo, heterociclilo o heteroarilo en cualquier atomo de ese grupo. Los sustituyentes adecuados incluyen, sin limitacion, halogeno, CN, NO2, OR15, SR15, S(O)2OR15, NR15R16, perfluoroalquilo C1-C2, perfluoroalcoxi C1-C2, 1,2-metilenodioxi, C(O)0r15, C(O)NR15R16, OC(O)NR15R16, NR15C(O)NR15R16, C(NR16)NR15R16, NR15C(NR16)NR15R16, S(O)2NR15R16, r17, C(O)R17, NR15C(O)R17, S(O)R17, S(O)2R17, R16, oxo, C(O)R16, C(O)(CH2)nOH, (CH2)nOR15, (CH2)nC(O)NR15R16, NR15S(O)2R17, donde n es independientemente 0-6 inclusive. Cada R15 es independientemente hidrogeno, alquilo C1-C4 o cicloalquilo C3-C6. Cada R16 es independientemente hidrogeno, cicloalquilo C3-C6, arilo, heterociclilo, heteroarilo, alquilo C1-C4 o alquilo C1-C4 sustituido con cicloalquilo C3-C6, arilo, heterociclilo o heteroarilo. Cada R17 es independientemente cicloalquilo C3-C6, arilo, heterociclilo, heteroarilo, alquilo C1-C4 o alquilo C1-C4 sustituido con cicloalquilo C3-C6, arilo, heterociclilo o heteroarilo. Cada cicloalquilo C3-C6, arilo, heterociclilo, heteroarilo y alquilo C1- C4 en cada R15, R16 y R17 puede estar opcionalmente sustituido con halogeno, CN, alquilo C1-C4, OH, alcoxi C1-C4, NH2, alquilamino C1-C4, dialquilamino C1-C4, perfluoroalquilo C1-C2, perfluoroalcoxi C1-C2 o 1,2-metilenodioxi.The term "substituents" refers to a "substituted" group in any functional group described herein, for example, an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocyclyl or heteroaryl group in any atom of that group. Suitable substituents include, without limitation, halogen, CN, NO2, OR15, SR15, S (O) 2OR15, NR15R16, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy, 1,2-methylenedioxy, C (O) 0r15, C ( O) NR15R16, OC (O) NR15R16, NR15C (O) NR15R16, C (NR16) NR15R16, NR15C (NR16) NR15R16, S (O) 2NR15R16, r17, C (O) R17, NR15C (O) R17, S ( O) R17, S (O) 2R17, R16, oxo, C (O) R16, C (O) (CH2) nOH, (CH2) nOR15, (CH2) nC (O) NR15R16, NR15S (O) 2R17, where n is independently 0-6 inclusive. Each R15 is independently hydrogen, C1-C4 alkyl or C3-C6 cycloalkyl. Each R16 is independently hydrogen, C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl or C1-C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each R17 is independently C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl, C1-C4 alkyl or C1-C4 alkyl substituted with C3-C6 cycloalkyl, aryl, heterocyclyl or heteroaryl. Each C3-C6 cycloalkyl, aryl, heterocyclyl, heteroaryl and C1-C4 alkyl in each R15, R16 and R17 may be optionally substituted with halogen, CN, C1-C4 alkyl, OH, C1-C4 alkoxy, NH2, C1-C4 alkylamino , C1-C4 dialkylamino, C1-C2 perfluoroalkyl, C1-C2 perfluoroalkoxy or 1,2-methylenedioxy.

En un aspecto, los sustituyentes en un grupo son independientemente, hidrogeno, hidroxilo, halogeno, nitro, SO3H, trifluorometilo, trifluorometoxi, alquilo (C1-C6 lineal o ramificado), alcoxi (C1-C6 lineal o ramificado), O-bencilo, O- fenilo, fenilo, 1,2-metilenodioxi, carboxilo, morfolinilo, piperidinilo, amino u OC(O)NR15R16. Cada R15 y R16 es como se ha descrito anteriormente.In one aspect, the substituents in a group are independently, hydrogen, hydroxyl, halogen, nitro, SO3H, trifluoromethyl, trifluoromethoxy, linear or branched (C1-C6) alkyl, linear or branched (C1-C6) alkoxy, O-benzyl, O-phenyl, phenyl, 1,2-methylenedioxy, carboxyl, morpholinyl, piperidinyl, amino or OC (O) NR15R16. Each R15 and R16 is as described above.

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El termino ''tratar1' o ''tratado1' se refiere a administrar un compuesto descrito en este documento a un sujeto con el proposito de curar, sanar, aliviar, mitigar, alterar, remediar, mejorar, beneficiar, o influir en una enfermedad, los smtomas de la enfermedad o la predisposicion hacia la enfermedad.The term "treat1" or "treated1" refers to administering a compound described herein to a subject for the purpose of curing, healing, alleviating, mitigating, altering, remedying, improving, benefiting, or influencing a disease, the symptoms of the disease or the predisposition towards the disease.

"Una cantidad eficaz" se refiere a una cantidad de un compuesto, que confiere un efecto terapeutico sobre el sujeto tratado. El efecto terapeutico puede ser objetivo (es decir, medible por algun ensayo o marcador) o subjetivo (es decir, el sujeto da un indicio de o siente un efecto). Una cantidad eficaz del compuesto descrito anteriormente puede variar de aproximadamente 0,1 mg/kg a aproximadamente 500 mg/kg. Las dosis eficaces tambien variaran dependiendo de la via de administracion, asi como la posibilidad de co-uso con otros agentes."An effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated subject. The therapeutic effect can be objective (that is, measurable by some trial or marker) or subjective (that is, the subject gives an indication of or feels an effect). An effective amount of the compound described above may vary from about 0.1 mg / kg to about 500 mg / kg. The effective doses will also vary depending on the route of administration, as well as the possibility of co-use with other agents.

imagen3image3

Los compuestos de la Tabla 1 tambien incluyen los siguientes:The compounds of Table 1 also include the following:

(1 -acetil-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3- carboxflico,(1-Acetyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H- pyrrole-3-carboxylic acid,

(1-metanosulfonil-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxflico,(1-Methanesulfonyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl- 1 H- pyrrole-3-carboxylic acid,

N-(2H-3,4,5,6-tetrahidropiran-4-il){5-[(5-fluoro-2-oxo(1 H-benzo[d]azolin-3-iliden))metil]-2,4-dimetilpirrol-3- il}carboxamida,N- (2H-3,4,5,6-tetrahydropyran-4-yl) {5 - [(5-fluoro-2-oxo (1 H-benzo [d] azolin-3-ylidene)) methyl] -2 , 4-dimethylpyrrol-3- yl} carboxamide,

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((S)-1-metanosulfonil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,((S) -1-methanesulfonyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1 H-Pyrrole-3-CarboxNico,

(1,1-dioxo-tetrahidro-tiofen-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,1,1-Dioxo-tetrahydro-thiophene-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl - 1 H-pyrrol-3-carboxNico,

(1-pirimidin-2-il-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H- pi^•ol-3-carbox^lico,5- [5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl (1-pyrimidin-2-yl-piperidin-4-yl) -amide -1 H- pi ^ • ol-3-carboxylic,

(3,4,5,6-tetrahidro-2H-[1,3']bipiridinil-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,(3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxyNico,

(4-hidroxi- 1,1-dioxo-tetrahidro-tiofen-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,(4-Hydroxy-1,1-dioxo-tetrahydro-thiophene-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2 , 4- dimethyl-1 H-pyrrole-3-carboxynic,

(1,1-dioxo- hexahidro-tiopiran-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,(1,1-dioxo-hexahydro-thiopiran-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl - 1 H-pyrrol-3-carboxNico,

((S)-6-oxo- piperidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol- 3-carboxNico,((S) -6-Oxo-piperidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1H-pyrrole-3-carboxyNico,

((2S,3S,4R,5S,6S)-3,4,5-trihidroxi-6-hidroximetil-tetrahidro-piran-2-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetiMH-pin'ol-3-carboxNico,((2S, 3S, 4R, 5S, 6S) -3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -amide of the acid 5- [5-fluoro-2-oxo-1, 2- dihydro-mdol- (3Z) -ylidenmethyl] -2,4-dimetiMH-pin'ol-3-carboxyNico,

[1-(2-hidroxi-acetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[1- (2-Hydroxy-acetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2.4 -dimethyl- 1 H -pyrrole-3-carboxyNico,

[(S)-1-(2-hidroxi- acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(S) -1- (2-Hydroxy-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4- dimethyl-1 H-pyrrole-3-carboxyNico,

(4-hidroxi-tetrahidro-furan-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H- pirrol-3-carbox^lico,5- (5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidemethyl] -2,4-dimethyl-1 acid (4-hydroxy-tetrahydro-furan-3-yl) -amide H- pyrrole-3-carboxylic acid,

((S)-2-oxo- pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol- 3-carboxNico,((S) -2-Oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1H-pyrrole-3-carboxyNico,

(1-bencil-4-hidroxi- pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,5- [5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidemethyl] -2,4-dimethyl (1-benzyl-4-hydroxy-pyrrolidin-3-yl) -amide - 1 H-pyrrol-3-carboxNico,

(1-acetil-4-hidroxi- pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,5- [5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidemethyl] -2,4-dimethyl (1-acetyl-4-hydroxy-pyrrolidin-3-yl) -amide - 1 H-pyrrol-3-carboxNico,

(1-dimetilaminooxalil-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,(1-Dimethylaminooxalyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H- pyrrole-3-carboxynic,

((S)-1-dimetilaminooxalil- pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,((S) -1-Dimethylaminooxalyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1 H-Pyrrole-3-CarboxNico,

((2S,3S,4R,5S)-3,4-dihidroxi-5-hidroximetil-tetrahidro-furan-2-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,((2S, 3S, 4R, 5S) -3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro- indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico,

((S)-1- carbamoilmetil-2-oxo-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,((S) -1- carbamoylmethyl-2-oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2 , 4- dimethyl-1 H-pyrrole-3-carboxynic,

[(S)-1-(2-hidroxi-etil)-2-oxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(S) -1- (2-Hydroxy-ethyl) -2-oxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxyNico,

[(R)-2-(2-hidroxietil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(R) -2- (2-Hydroxyethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmetil] -

2,4-dimetil-1 H-pirrol-3-carbox^lico,2,4-dimethyl-1 H-pyrrole-3-carboxylic acid,

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((R)-2-carbamoilmetil-3-oxo-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-((R) -2-carbamoylmethyl-3-oxo-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carboxilico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(R)-2-(2-metoxi-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(R) -2- (2-Methoxy-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ilidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

((R)-3-oxo-2-piridin-3-ilmetil-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-((R) -3-Oxo-2-pyridin-3-ylmethyl-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmetil] -

2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(R)-3-oxo-2- (tetrahidro-piran-4-il)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(R) -3-Oxo-2- (tetrahydro-pyran-4-yl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic,

[(R)-3-oxo-2-(tetrahidro-furan-3-il)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(R) -3-Oxo-2- (tetrahydro-furan-3-yl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic,

[1-(morfolina-4-carbonil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[1- (Morpholine-4-carbonyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2.4 - dimethyl-1 H-pyrrole-3-carboxynic,

[(S)-l-(morfolina- 4-carbonil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-[(S) -l- (morpholine-4-carbonyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carboxilico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

dimetilamida del acido 4-({5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3-carbonil}- amino)-piperidina-1-carbox^lico,Acid dimethylamide 4 - ({5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrol-3-carbonyl} -amino ) -piperidine-1-carboxylic acid,

((S)-1-dimetilcarbamoil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,((S) -1-Dimethylcarbamoyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1 H-Pyrrole-3-CarboxNico,

[1-(2-metoxi-acetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[1- (2-Methoxy-acetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2.4 -dimethyl- 1 H -pyrrole-3-carboxyNico,

[(S)-1-(2-metoxi-acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxilico,[(S) -1- (2-Methoxy-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxylic acid,

N-((3R)oxolan-3-il){5-[(5-fluoro-2-oxo(1H-benzo[d] azolin-3-ilideno))metil]-2,4-dimetilpirrol-3-il}carboxamida,N - ((3R) oxolan-3-yl) {5 - [(5-fluoro-2-oxo (1 H -benzo [d] azolin-3-ylidene)) methyl] -2,4-dimethylpyrrol-3-yl carboxamide,

[(R)-2-(2-morfolin-4-il-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(R) -2- (2-Morpholin-4-yl-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro- indole- (3Z) - ylidenemethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico,

[(S)-1-(2-metoxietil)-2-oxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(S) -1- (2-Methoxyethyl) -2-oxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxNico,

((S)-2-oxo-1-piridin-4-ilmetil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxilico,((S) -2-Oxo-1-pyridin-4-ylmethyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(R)-3-oxo-2-(tetrahidro-piran-4-ilmetil)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(R) -3-Oxo-2- (tetrahydro-pyran-4-ylmethyl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic,

[(S)-1-(2-metoxi-etil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[(S) -1- (2-Methoxy-ethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H -pyrrole-3-carboxyNico,

[1-(2-metoxi-etil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H- pirrol-3-carbox^lico,[1- (2-Methoxy-ethyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2.4 -dimethyl-1H-pyrrole-3-carboxylic acid,

[1-(2-dimetilamino-acetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[1- (2-Dimethylamino-acetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4 - dimethyl-1 H-pyrrole-3-carboxynic,

[(S)-1-(2-dimetilamino-acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(S) -1- (2-Dimethylamino-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

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(6'-metil-3,4,5,6-tetrahidro-2H-[1,3']bipiridinil-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,5- (5-Fluoro-2-oxo-1,2-dihydro) acid (6'-methyl-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-4-yl) -amide -indole- (3Z) -lidenemethyl] -2,4-dimethyl-1H-pyrrole-3-carboxyNico,

[(S)-1-(6-metil-piridin-3-il)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(S) -1- (6-methyl-pyridin-3-yl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxyNico,

[(S)-2-oxo-1-(tetrahidro-piran-4-ilmetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(S) -2-Oxo-1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic,

[1-(2-metanosulfonil-etil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[1- (2-Methanesulfonyl-ethyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2,4 - dimethyl-1 H-pyrrole-3-carboxynic,

[(S)-1-(2-metanosulfonil-etil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(S) -1- (2-Methanesulfonyl-ethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4- dimethyl-1 H-pyrrole-3-carboxyNico,

[(R)-2-(2-metanosulfonil-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(R) -2- (2-Methanesulfonyl-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico,

[(S)-2-(2-metoxi-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(S) -2- (2-Methoxy-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ilidenmethyl] -

2.4- dimetil-1 H-pirroi^-carboxilico,2.4-dimethyl-1 H-pyrroi ^ -carboxylic acid,

[(R)-2-(2-etoxi-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(R) -2- (2-Ethoxy-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxyNico,

[(S)-1-(2-metoxi-etil)-2,5-dioxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(S) -1- (2-Methoxy-ethyl) -2,5-dioxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ilidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(R)-3-oxo-2-(tetrahidro-furan-3-ilmetil)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(R) -3-Oxo-2- (tetrahydro-furan-3-ylmethyl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic,

[(R)-3-oxo-2-(tetrahidro-furan-2-ilmetil)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetiMH-pirrol-3-carboxNico,[(R) -3-Oxo-2- (tetrahydro-furan-2-ylmethyl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimetiMH-pyrrole-3-carboxyNico,

[(S)-2,5-dioxo-1-(tetrahidro-piran-4-ilmetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetiMH-pirrol-3-carboxNico,[(S) -2,5-dioxo-1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro- indole- (3Z) - ylidenemethyl] -2,4-dimetiMH-pyrrole-3-carboxNico,

[(S)-2,5-dioxo-1-(tetrahidro-piran-4-il)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetiMH-pirrol-3-carboxNico,[(S) -2,5-dioxo-1- (tetrahydro-pyran-4-yl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro- indole- (3Z) - ylidenemethyl] -2,4-dimetiMH-pyrrole-3-carboxNico,

((S)-1-dimetilcarbamoil-2-oxo-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-((S) -1-Dimethylcarbamoyl-2-oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carboxflico.2.4-dimethyl-1 H-pyrrole-3-carboxylic.

Los compuestos de la Tabla 1 tambien incluyen los siguientes:The compounds of Table 1 also include the following:

(4-hidroxi-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3- carboxNico,(4-Hydroxy-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1 H-pyrrole-3- carboxNico,

(4-amino-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3- carboxilico,(4-Amino-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1 H-pyrrole-3- carboxylic,

(4-oxo-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3- carboxNico,(4-Oxo-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3- carboxNico,

((1 S,2S)-2-hidroxi-ciclopentil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H- pirrol-3-carboxilico,((1 S, 2S) -2-hydroxy-cyclopentyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl- 1 H- pyrrole-3-carboxylic acid,

((1 S,2R)-2-hidroxi-ciclopentil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-H- pirrol-3-carbox^lico,((1 S, 2R) -2-Hydroxy-cyclopentyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- H- pyrrole-3-carboxylic acid,

(4-acetilamino-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol- 3-carboxNico,(4-Acetylamino-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3- carboxNico,

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((1S,2S)-2-hidroxiciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H- pirrol-3-carbox^lico,((1S, 2S) -2-hydroxycyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1H-pyrrole -3-carboxylic,

[4-(morfolina-4-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[4- (Morpholine-4-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H-Pyrrole-3-CarboxNico,

[4-(pirrolidina-1-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[4- (Pyrrolidine-1-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-Pyrrole-3-CarboxNico,

[4-(aziridina-1-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[4- (Aziridine-1-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H-Pyrrole-3-CarboxNico,

[(1R,3S)-3-(pirrolidina-1-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(1R, 3S) -3- (Pyrrolidine-1-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(1R,3S)-3-(morfolina-4- carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(1R, 3S) -3- (morpholine-4- carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carboxilico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(1R,3S)-3- (aziridina-1-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(1R, 3S) -3- (aziridine-1-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(1R,2S)-2-(pirrolidina-1-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(1R, 2S) -2- (pyrrolidine-1-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(1 R,2S)-2-(morfolina-4-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(1 R, 2S) -2- (morpholine-4-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid,

[(1R,2S)-2-(aziridina-1-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(1R, 2S) -2- (aziridine-1-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2.4- dimetil-1 H-pirrol-3-carbox^lico.2.4-dimethyl-1 H-pyrrole-3-carboxylic.

En las estructuras de la tabla anterior, la union del grupo R es a traves del atomo de nitrogeno amino representado como "NH2" y, por lo tanto, significa que el resto unido al grupo carbonilo representado como un "grupo -N-dclico" donde el grupo ciclico es cicloalquilo, cicloalquenilo, heterociclo (cualquier de los cuales puede estar sustituido).In the structures of the previous table, the union of the R group is through the amino nitrogen atom represented as "NH2" and, therefore, means that the remainder attached to the carbonyl group represented as a "N-dical group" where the cyclic group is cycloalkyl, cycloalkenyl, heterocycle (any of which may be substituted).

Los compuestos moduladores de quinasa pueden identificarse a traves de metodos tanto in vitro (por ejemplo, basados en celulas y no basados en celulas) como in vivo. Se describen ejemplos representativos de estos metodos en los Ejemplos de este documento.The kinase modulating compounds can be identified by methods both in vitro (for example, based on cells and not based on cells) and in vivo. Representative examples of these methods are described in the Examples of this document.

Combinaciones de sustituyentes y variables ideados por esta invencion son solamente aquellos que provocan la formacion de compuestos estables. El termino "estable", como se usa en este documento, se refiere a compuestos que poseen estabilidad suficiente para permitir la fabricacion y que mantienen la integridad del compuesto durante un periodo suficiente de tiempo para ser utiles para los propositos detallados en este documento (por ejemplo, administracion terapeutica o profilactica a un sujeto).Combinations of substituents and variables devised by this invention are only those that cause the formation of stable compounds. The term "stable", as used herein, refers to compounds that have sufficient stability to allow manufacturing and that maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed in this document (for example, therapeutic or prophylactic administration to a subject).

Los compuestos descritos en el presente documento pueden sintetizarse usando metodos convencionales, como se ilustra en los esquemas en el presente documento. En los esquemas en el presente documento, a menos que se defina expresamente otra cosa, las variables en las formulas quimicas corresponden a posiciones similares como se define en otras formulas en el presente documento.The compounds described herein can be synthesized using conventional methods, as illustrated in the schemes herein. In the schemes in this document, unless expressly defined otherwise, the variables in the chemical formulas correspond to similar positions as defined in other formulas herein.

Los compuestos sintetizados pueden separarse de una mezcla de reaccion y purificarse adicionalmente por un metodo tal como cromatografia en columna, cromatografia liquida a alta presion o recristalizacion. Como puede apreciarse por el experto en la tecnica, metodos adicionales de sintetizacion de los compuestos de las formulas en el presente documento seran evidentes para los expertos en la tecnica. Ademas, las diversas etapas sinteticas pueden realizarse en una secuencia u orden alterno para dar los compuestos deseados. Las transformaciones quimicas sinteticas y las metodologias de grupo protector (protection y desproteccion) utiles en la sintetizacion de los compuestos descritos en el presente documento se conocen en la tecnica e incluyen, por ejemplo, las que se describen en R. Larock, Comprehensive Organic Transformations, 2a Ed., Wiley-VCH Publishers (1999); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3a Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1999); y L. Paquette, ed., Enciclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), y ediciones posteriores de los mismos. Los compuestos de esta invencion pueden contener uno o mas centros asimetricos y, por lo tanto, pueden aparecer como racematos y mezclas racemicas, enantiomeros individuales, diastereomeros individuales y mezclas diastereomericas. Todas estas formas isomericas de estos compuestos se incluyen expresamente en la presenteThe synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid chromatography or recrystallization. As can be appreciated by those skilled in the art, additional methods of synthesizing the compounds of the formulas herein will be apparent to those skilled in the art. In addition, the various synthetic steps can be performed in an alternate sequence or order to give the desired compounds. Synthetic chemical transformations and protective group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations , 2nd Ed., Wiley-VCH Publishers (1999); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and later editions thereof. The compounds of this invention may contain one or more asymmetric centers and, therefore, may appear as racemates and racemic mixtures, individual enantiomers, individual diastereomers and diastereomeric mixtures. All these isomeric forms of these compounds are expressly included herein.

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invention. Los compuestos de esta invention tambien pueden representarse en multiples formas tautomericas, en tales casos, la invencion incluye expresamente todas las formas tautomericas de los compuestos descritos en el presente documento. Todas estas formas isomericas de dichos compuestos se incluyen adicionalmente en la presente invencion. Todas las formas cristalinas de los compuestos descritos en el presente documento se incluyen expresamente en la presente invencion.invention. The compounds of this invention can also be represented in multiple tautomeric forms, in such cases, the invention expressly includes all tautomeric forms of the compounds described herein. All these isomeric forms of said compounds are further included in the present invention. All crystalline forms of the compounds described herein are expressly included in the present invention.

El alcance de la presente invencion se define por las reivindicaciones y se refiere a los compuestos de formula III. En la presente tambien se desvelan derivados o profarmacos farmaceuticamente aceptables de los mismos. Un "derivado o profarmaco farmaceuticamente aceptable" se refiere a cualquier sal, ester, sal de un ester, u otro derivado farmaceuticamente aceptable de un compuesto de esta invencion que, tras la administration a un receptor, es capaz de proporcionar (directa o indirectamente) un compuesto de esta invencion. Los derivados y profarmacos particularmente favoritos son los que aumentan la biodisponibilidad de los compuestos de esta invencion cuando dichos compuestos se administran a un mamifero (por ejemplo, permitiendo que un compuesto administrado por via oral se absorba mas facilmente en la sangre) o que mejoren la administracion del precursor a un compartimento biologico (por ejemplo, el cerebro o el sistema linfatico) con respecto a las especies precursoras. Los profarmacos preferidos incluyen derivados en los que un grupo que mejora la solubilidad acuosa o el transporte activo a traves de la membrana intestinal se adjunta a la estructura de las formulas descritas en el presente documento. Veanse, por ejemplo, Alexander, J. y col. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs, Elsevier: Amsterdam, 1985; pags. 1-92; Bundgaard, H.; Nielsen, N. M. Journal of Medicinal Chemistry 1987, 30, 451454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Publ.: Suiza, 1991; pags. 113-191; Digenis, G. A. y col. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G. J.; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed.; Overseas Publ.: Amsterdam, 1996; pags. 351-385; Pitman, I. H. Medicinal Research Reviews 1981, 1, 189-214; Sinkula, A. A.; Yalkowsky. Journal of Pharmaceutical Sciences 1975, 64, 181-210; Verbiscar, A. J.; Abood, L. G Journal of Medicinal Chemistry 1970, 13, 1176-1179; Stella, V. J.; Himmelstein, K. J. Journal of Medicinal Chemistry 1980, 23, 1275-1282; Bodor, N.; Kaminski, J. J. Annual Reports in Medicinal Chemistry 1987, 22, 303-313.The scope of the present invention is defined by the claims and refers to the compounds of formula III. Pharmaceutically acceptable derivatives or prodrugs thereof are also disclosed herein. A "pharmaceutically acceptable derivative or prodrug" refers to any salt, ester, salt of an ester, or other pharmaceutically acceptable derivative of a compound of this invention which, upon administration to a recipient, is capable of providing (directly or indirectly) a compound of this invention. Particularly preferred derivatives and prodrugs are those that increase the bioavailability of the compounds of this invention when said compounds are administered to a mammal (for example, allowing a compound administered orally to be absorbed more easily in the blood) or to improve the administration of the precursor to a biological compartment (for example, the brain or the lymphatic system) with respect to the precursor species. Preferred prodrugs include derivatives in which a group that improves aqueous solubility or active transport through the intestinal membrane is attached to the structure of the formulas described herein. See, for example, Alexander, J. et al. Journal of Medicinal Chemistry 1988, 31, 318-322; Bundgaard, H. Design of Prodrugs, Elsevier: Amsterdam, 1985; P. 1-92; Bundgaard, H .; Nielsen, N. M. Journal of Medicinal Chemistry 1987, 30, 451454; Bundgaard, H. A Textbook of Drug Design and Development; Harwood Academic Pub .: Switzerland, 1991; P. 113-191; Digenis, G. A. et al. Handbook of Experimental Pharmacology 1975, 28, 86-112; Friis, G. J .; Bundgaard, H. A Textbook of Drug Design and Development; 2 ed .; Overseas Publ .: Amsterdam, 1996; P. 351-385; Pitman, I. H. Medicinal Research Reviews 1981, 1, 189-214; Sinkula, A. A .; Yalkowsky Journal of Pharmaceutical Sciences 1975, 64, 181-210; Verbiscar, A. J .; Abood, L. G Journal of Medicinal Chemistry 1970, 13, 1176-1179; Stella, V. J .; Himmelstein, K. J. Journal of Medicinal Chemistry 1980, 23, 1275-1282; Bodor, N .; Kaminski, J. J. Annual Reports in Medicinal Chemistry 1987, 22, 303-313.

Los compuestos de esta invencion pueden modificarse anadiendo funcionalidades apropiadas para mejorar las propiedades biologicas selectivas. Dichas modificaciones se conocen en la tecnica e incluyen aquellas que aumentan la penetration biologica en un compartimento biologico dado (por ejemplo, la sangre, el sistema linfatico, el sistema nervioso), aumentan la disponibilidad oral, aumentan la solubilidad para permitir la administracion por inyeccion, alteran el metabolismo y alteran la tasa de excretion.The compounds of this invention can be modified by adding appropriate functionalities to improve the selective biological properties. Such modifications are known in the art and include those that increase biological penetration in a given biological compartment (e.g., blood, lymphatic system, nervous system), increase oral availability, increase solubility to allow administration by injection. , alter the metabolism and alter the rate of excretion.

Las sales farmaceuticamente aceptables de los compuestos de esta invencion incluyen aquellas obtenidas a partir de acidos y bases inorganicas y organicas farmaceuticamente aceptables. Los ejemplos de sales de acidos adecuadas incluyen acetato, adipato, alginato, aspartato, benzoato, bencenosulfonato, bisulfato, butirato, citrato, alcanforato, alcanforsulfonato, digluconato, dodecilsulfato, etanosulfonato, formiato, fumarato, glucoheptanoato, glicolato, hemisulfato, heptanoato, hexanoato, clorhidrato, bromhidrato, yodhidrato, 2-hidroxietanosulfonato, lactato, maleato, malonato, metanosulfonato, 2-naftalenosulfonato, nicotinato, nitrato, palmoato, pectinato, persulfato, 3- fenilpropionato, fosfato, picrato, pivalato, propionato, salicilato, succinato, sulfato, tartrato, tiocianato, tosilato y undecanoato. Otros acidos, tales como, oxalico, aunque no son farmaceuticamente aceptables por si mismos, pueden emplearse en la preparacion de sales utiles como intermedios en la obtencion de los compuestos de la invencion y sus sales de adicion de acidos farmaceuticamente aceptables. Las sales obtenidas a partir de las bases apropiadas incluyen sales de metales alcalinos (por ejemplo, sodio), metales alcalinoterreos (por ejemplo, magnesio), amonio y N-(alquil)4+. Esta invencion tambien preve la cuaternizacion de cualquier grupo que contiene nitrogeno basico de los compuestos desvelados en el presente documento. Los productos solubles en agua o aceite o dispersables pueden obtenerse por dicha cuaternizacion.Pharmaceutically acceptable salts of the compounds of this invention include those obtained from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, campforate, camphorsulfonate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycolate, hemisulfate, heptane hydrochloride, hydrobromide, iodhydrate, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3- phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, succinate tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, although not pharmaceutically acceptable in themselves, can be used in the preparation of useful salts as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts obtained from the appropriate bases include alkali metal salts (for example, sodium), alkaline earth metals (for example, magnesium), ammonium and N- (alkyl) 4+. This invention also provides for the quaternization of any group containing basic nitrogen of the compounds disclosed herein. Water or oil soluble or dispersible products can be obtained by said quaternization.

Los compuestos de las formulas descritas en este documento pueden administrarse, por ejemplo, por inyeccion, via intravenosa, intraarterial, subdermica, intraperitoneal, intramuscular, o subcutanea; o por via oral, bucal, nasal, transmucosa, topica, en una preparation oftalmica, o por inhalation, con una dosificacion que varia de aproximadamente 0,5 a aproximadamente 100 mg/kg de peso corporal, como alternativa dosificaciones entre 1 mg y 1000 mg por dosis, cada 4 a 120 horas, o de acuerdo con las necesidades del farmaco particular. Los metodos de este documento contemplan la administracion de una cantidad eficaz de compuesto o composition de compuestos para conseguir el efecto deseado o indicado. Normalmente, las composiciones farmaceuticas de esta invencion se administraran de aproximadamente 1 a aproximadamente 6 veces al dia o como alternativa, como una infusion continua. Dicha administracion puede usarse como terapia cronica o aguda. La cantidad de ingrediente activo que puede combinarse con los materiales de vehiculo para producir una forma monodosis variara dependiendo del hospedador tratado y el modo particular de administracion. Una preparacion tipica contendra de aproximadamente un 5 % a aproximadamente un 95 % de compuesto activo (p/p). Como alternativa, dichas preparaciones comprenden de aproximadamente un 20 % a aproximadamente un 80 % de compuesto activo.The compounds of the formulas described herein can be administered, for example, by injection, intravenously, intraarterially, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, orally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.5 to about 100 mg / kg body weight, as an alternative dosages between 1 mg and 1000 mg per dose, every 4 to 120 hours, or according to the needs of the particular drug. The methods of this document contemplate the administration of an effective amount of compound or composition of compounds to achieve the desired or indicated effect. Normally, the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times a day or as an alternative, as a continuous infusion. Such administration can be used as chronic or acute therapy. The amount of active ingredient that can be combined with the vehicle materials to produce a single dose form will vary depending on the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w / w). Alternatively, said preparations comprise from about 20% to about 80% active compound.

Pueden requerirse dosis inferiores o mayores que las indicadas anteriormente. Los regimenes especificos de dosificacion y tratamiento para cualquier paciente particular dependeran de diversos factores, incluyendo la actividad del compuesto especifico empleado, la edad, peso corporal, estado de salud general, sexo, dieta, tiempo de administracion, tasa de excrecion, combination de farmacos, la gravedad y curso de la enfermedad, afeccion oLower or higher doses than those indicated above may be required. The specific dosing and treatment regimens for any particular patient will depend on various factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, administration time, excretion rate, combination of drugs. , the severity and course of the disease, condition or

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smtomas, la disposicion del paciente a la enfermedad, afeccion o smtomas, y el juicio del medico tratante.symptoms, the patient's disposition to the disease, condition or symptoms, and the judgment of the attending physician.

Tras la mejora de la afeccion del paciente, puede administrate una dosis de mantenimiento de un compuesto, composition o combination de esta invention, si fuera necesario. Posteriormente, la dosificacion o frecuencia de administration, o ambas, pueden reducirse, como una funcion de los smtomas, hasta un nivel al cual se retiene la afeccion mejorada, cuando los smtomas se han aliviado hasta el nivel deseado, debe cesarse el tratamiento. Los pacientes pueden requerir, sin embargo, tratamiento intermitente en una base a largo plazo tras cualquier recidiva de los smtomas de la enfermedad.After the improvement of the patient's condition, a maintenance dose of a compound, composition or combination of this invention can be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained, when the symptoms have been relieved to the desired level, treatment should be stopped. Patients may, however, require intermittent treatment on a long-term basis after any recurrence of disease symptoms.

Las composiciones definidas en este documento, incluyen los compuestos de las formulas definidas en este documento, asi como agentes terapeuticos adicionales si estuvieran presentes, en cantidades eficaces para conseguir una modulation de la enfermedad o smtomas de la enfermedad, incluyendo trastornos mediados por quinasa o smtomas de los mismos. Referencias que incluyen ejemplos de agentes terapeuticos adicionales son: 1) Burger's Medicinal Chemistry & Drug Discovery 6a edition, de Alfred Burger, Donald J. Abraham, ed., Volumenes 1 a 6, Wiley Interscience Publication, NY, 2003. Agentes terapeuticos adicionales incluyen, aunque sin limitation, agentes de enfermedades, trastornos o smtomas de los mismos incluyendo, por ejemplo, agentes anticancer, agentes antiproliferativos, agentes antineoplasicos, agentes antitumorales, agentes antineoplasicos tipo antimetabolito/inhibidor de timidilato sintasa, agentes antineoplasicos tipo alquilantes, agentes antineoplasicos tipo antibiotico, o cualquier otro agentes normalmente administrado como agente principal o adyuvante en protocolos de tratamiento del cancer (por ejemplo, antiemetico, antianemia, etc.), incluyendo, por ejemplo, sulfato de vinblastina, vincristina, vindesina, vinestramida, vinorelbina, vintriptol, vinzolidina, tamoxifeno, toremifeno, raloxifeno, droloxifeno, yodoxifeno, acetato de megestrol, anastrozol, letrazol, borazol, exemestano, flutamida, nilutamida, bicalutamida, acetato ciproterona, acetato de goserelina, luprolida, finasterida, herceptina, metotrexato, 5-fluorouracilo, arabinosido de citosina, doxorrubicina, daunomicina, epirrubicina, idarrubicina, mitomicina-C, dactinomicina, mitramicina, cisplatino, carboplatino, melfalan, clorambucilo, busulfan, ciclofosfamida, ifosfamida, nitrosoureas, tiotefan, vincristina, taxol, taxotere, etoposido, teniposido, amsacrina, irinotecano, topotecano, una epotilona, Iressa, Avastin, OSI-774, inhibidores de angiogenesis, inhibidores de EGF, inhibidores de MEK, inhibidores de VEGF, inhibidores de CDK, inhibidores de Her1 y Her2 y anticuerpos monoclonales.The compositions defined herein include the compounds of the formulas defined herein, as well as additional therapeutic agents if present, in amounts effective to achieve a modulation of the disease or disease symptoms, including kinase-mediated disorders or symptoms. thereof. References that include examples of additional therapeutic agents are: 1) Burger's Medicinal Chemistry & Drug Discovery 6a edition, by Alfred Burger, Donald J. Abraham, ed., Volumes 1 to 6, Wiley Interscience Publication, NY, 2003. Additional therapeutic agents include , but without limitation, disease agents, disorders or symptoms thereof including, for example, anti-cancer agents, anti-proliferative agents, anti-cancer agents, anti-tumor agents, anti-tumor agents antimetabolite / thymidylate synthase, anti-neoplastic agents type alkylating agents, anti-cancer agents antibiotic, or any other agents normally administered as the main agent or adjuvant in cancer treatment protocols (for example, antiemetic, antianemia, etc.), including, for example, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, tamoxifen, toremifene, raloxifene, droloxifene, iodoxifene, Megestrol Acetate, Anastrozole, Letrazol, Borazol, Exemestane, Flutamide, Nilutamide, Bicalutamide, Cyproterone Acetate, Goserelin Acetate, Luprolide, Finasteride, Herceptin, Methotrexate, 5-Fluorouracil, Cytosine Arabinoside, Doxorubicin, Mitomycinubicin, Mitochromiccin -C, dactinomycin, mitramycin, cisplatin, carboplatin, melphalan, chlorambucil, busulfan, cyclophosphamide, ifosfamide, nitrosoureas, thiotefan, vincristine, taxol, taxotere, etoposide, teniposide, amsacrine, irinotecan, toponane, an eponatin, osonatin, eponatin, avaonastine, an eponatin, an eponatin, an eponatin, an eponatin 774, angiogenesis inhibitors, EGF inhibitors, MEK inhibitors, VEGF inhibitors, CDK inhibitors, Her1 and Her2 inhibitors and monoclonal antibodies.

La expresion "vehiculo o adyuvante farmaceuticamente aceptable" se refiere a un vehiculo o adyuvante que puede administrarse a un paciente, junto con un compuesto de esta invencion, y que no destruye la actividad farmacologica del mismo y es no toxico cuando se administra en dosis suficientes para suministrar una cantidad terapeutica del compuesto.The term "pharmaceutically acceptable carrier or adjuvant" refers to a vehicle or adjuvant that can be administered to a patient, together with a compound of this invention, and which does not destroy the pharmacological activity thereof and is non-toxic when administered in sufficient doses. to deliver a therapeutic amount of the compound.

Los medios, adyuvantes y vehiculos farmaceuticamente aceptables que pueden usarse en las composiciones farmaceuticas de esta invencion incluyen, aunque sin limitacion, intercambiadores de iones, alumina, estearato de aluminio, lecitina, sistemas de suministro de farmacos auto-emulsionantes (SEDDS) tales como succinato de polietilenglicol 1000 de d-a-tocoferol, tensioactivos usados en formas farmaceuticas de dosificacion tales como Tween u otras matrices similares de suministro polimerico, proteinas sericas, tales como albumina serica humana, sustancias tamponantes tales como fosfatos, glicina, acido sorbico, sorbato potasico, mezclas parciales de gliceridos de acidos grasos vegetales saturados, agua, sales o electrolitos, tales como sulfato de protamina, hidrogenofosfato disodico, hidrogenofosfato potasico, cloruro sodico, sales de cinc, silice coloidal, trisilicato de magnesio, polivinilpirrolidona, sustancias basadas en celulosa, polietilenglicol, carboximetilcelulosa sodica, poliacrilatos, ceras, polimeros de bloque de polietileno-polioxipropileno, polietilenglicol y lanolina. Tambien pueden usarse de forma ventajosa ciclodextrinas tales como a-, p-, y Y-ciclodextrina, o derivados quimicamente modificados tales como hidroxialquilciclodextrinas, incluyendo 2- y 3-hidroxipropil-p-ciclodextrinas, u otros derivados solubilizados, para potenciar el suministro de compuestos de las formulas descritas en este documento.Pharmaceutically acceptable media, adjuvants and vehicles that can be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as succinate. of polyethylene glycol 1000 of da-tocopherol, surfactants used in pharmaceutical dosage forms such as Tween or other similar polymeric delivery matrices, serine proteins, such as human serum albumin, buffering substances such as phosphates, glycine, sorbic acid, potassium sorbate, mixtures Partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacr ilates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and lanolin. Cyclodextrins such as a-, p-, and Y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-p-cyclodextrins, or other solubilized derivatives, can also be used advantageously to enhance the supply of compounds of the formulas described in this document.

Las composiciones farmaceuticas de esta invencion pueden administrarse por via oral, parenteral, por pulverization de inhalation, por via topica, rectal, nasal, bucal, vaginal o mediante un deposito implantado, preferiblemente por administracion oral o administracion por inyeccion. Las composiciones farmaceuticas de esta invencion pueden contener cualquier medio, adyuvante o vehiculo no toxico farmaceuticamente aceptable convencional. En algunos casos, el pH de la formulation puede ajustarse con acidos, bases o tampones farmaceuticamente aceptables para potenciar la estabilidad del compuesto formulado o su forma de suministro. El termino parenteral como se usa en este documento incluye inyeccion subcutanea, intracutanea, intravenosa, intramuscular, intraarticular, intraarterial, intrasinobial, intraesternal, intratecal, intralesional e intracraneal o tecnicas de infusion.The pharmaceutical compositions of this invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally or by an implanted deposit, preferably by oral administration or by injection administration. The pharmaceutical compositions of this invention may contain any conventional pharmaceutically acceptable non-toxic medium, adjuvant or vehicle. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form. The term parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasinobial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.

Las composiciones farmaceuticas pueden estar en forma de una preparation inyectable esteril, por ejemplo, en forma de una suspension acuosa u oleaginosa inyectable esteril. Esta suspension puede formularse de acuerdo con tecnicas conocidas en la tecnica usando agentes de dispersion o humectantes adecuados (tales como, por ejemplo, Tween 80) y agentes de suspension. La preparacion inyectable esteril tambien puede ser una solution o suspension inyectable esteril en un diluyente o disolvente no toxico parenteralmente aceptable, por ejemplo, como una solucion en 1,3-butanodiol. Entre los vehiculos y disolventes aceptables que pueden emplearse estan manitol, agua, solucion de Ringer y solucion isotonica de cloruro sodico. Ademas, se emplean convencionalmente aceites esteriles fijos como disolvente o medio de suspension. Para este proposito, puede emplearse cualquier aceite fijo blando incluyendo mono o digliceridos sinteticos. Los acidos grasos, tales como acido oleico y sus derivados de gliceridosThe pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to techniques known in the art using suitable dispersing agents or humectants (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, fixed sterile oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil including synthetic mono or diglycerides can be used. Fatty acids, such as oleic acid and its glyceride derivatives

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son utiles en la preparacion de inyectables, y son aceites farmaceuticamente aceptables naturales, tales como aceite de oliva o aceite de ricino, especialmente en sus versiones polioxietiladas. Estas soluciones o suspensiones oleosas tambien pueden contener un diluyente o dispersante de alcohol de cadena larga, o carboximetilcelulosa o agente de dispersion similar que se usa habitualmente en la formulacion de formas de dosificacion farmaceuticamente aceptables tales como emulsiones y/o suspensiones. Otros tensioactivos habitualmente usados tales como Tween o Spans y/u otros agentes similares emulsionantes o potenciadores de la biodisponibilidad que se usan habitualmente en la fabricacion de formas de dosificacion farmaceuticamente aceptables solidas, liquidas, u otras formas de dosificacion tambien pueden usarse para propositos de formulacion.they are useful in the preparation of injectables, and are naturally pharmaceutically acceptable oils, such as olive oil or castor oil, especially in its polyoxyethylated versions. These oily solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, or carboxymethyl cellulose or similar dispersing agent that is commonly used in the formulation of pharmaceutically acceptable dosage forms such as emulsions and / or suspensions. Other commonly used surfactants such as Tween or Spans and / or other similar emulsifying or bioavailability enhancing agents that are commonly used in the manufacture of solid, liquid pharmaceutically acceptable dosage forms or other dosage forms can also be used for formulation purposes. .

Las composiciones farmaceuticas de esta invencion pueden administrarse por via oral en cualquier forma de dosificacion oralmente aceptable incluyendo, aunque sin limitacion, capsulas, comprimidos, emulsiones y suspensiones acuosas, dispersiones y soluciones. En el caso de comprimidos para uso oral, los vehiculos que se usan habitualmente incluyen lactosa y almidon de maiz. Normalmente tambien se anaden agentes lubricantes, tales como estearato de magnesio. Para administracion oral en una forma de capsula, los diluyentes utiles incluyen lactosa y almidon de maiz deshidratado. Cuando se administran suspensiones y/o emulsiones acuosas por via oral, el ingrediente activo puede suspenderse o disolverse en una fase oleosa, se combina con agentes de emulsion y/o suspension. Si se desea, pueden anadirse ciertos agentes edulcorantes y/o aromatizantes y/o colorantes.The pharmaceutical compositions of this invention can be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, emulsions and aqueous suspensions, dispersions and solutions. In the case of tablets for oral use, commonly used vehicles include lactose and corn starch. Normally, lubricating agents, such as magnesium stearate, are also added. For oral administration in a capsule form, useful diluents include lactose and dehydrated corn starch. When aqueous suspensions and / or emulsions are administered orally, the active ingredient can be suspended or dissolved in an oil phase, combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

Las composiciones farmaceuticas de esta invencion tambien pueden administrarse en forma de supositorios para administracion rectal. Estas composiciones pueden prepararse mezclando un compuesto de esta invencion con un excipiente no irritante adecuado que es solido a temperatura ambiente pero liquido a temperatura rectal y, por lo tanto, se fundira en el recto para liberar los componentes activos. Dichos materiales incluyen, aunque sin limitacion, manteca de cacao, cera de abejas y polietilenglicoles.The pharmaceutical compositions of this invention can also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and, therefore, will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.

La administracion topica de las composiciones farmaceuticas de esta invencion es util cuando el tratamiento deseado implica areas u organos facilmente accesibles por aplicacion topica. Para aplicacion topica a la piel, la composition farmaceutica debe formularse con una pomada adecuada que contiene los componentes activos suspendidos o disueltos en un vehiculo. Los vehiculos para administracion topica de los compuestos de esta invencion incluyen, aunque sin limitacion, aceite mineral, vaselina liquida, vaselina blanca, propilenglicol, compuesto de polioxietileno polioxipropileno, cera emulsionante y agua. Como alternativa, la composicion farmaceutica puede formularse con una locion o crema adecuada que contiene el compuesto activo suspendido o disuelto en un vehiculo con agentes emulsionantes adecuados. Los vehiculos adecuados incluyen, aunque sin limitacion, aceite mineral, monoestearato de sorbitan, polisorbato 60, cera de esteres cetilicos, alcohol cetearilico, 2-octildodecanol, alcohol bencilico y agua. Las composiciones farmaceuticas de esta invencion tambien pueden aplicarse de forma topica al tracto intestinal inferior por formulacion de supositorio rectal o en una formulacion adecuada de enema. Tambien se incluyen parches topicos-transdermicos en esta invencion.The topical administration of the pharmaceutical compositions of this invention is useful when the desired treatment involves areas or organs easily accessible by topical application. For topical application to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing active components suspended or dissolved in a vehicle. Vehicles for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition may be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a vehicle with suitable emulsifying agents. Suitable vehicles include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention can also be applied topically to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topical-transdermal patches are also included in this invention.

Las composiciones farmaceuticas de esta invencion pueden administrarse por aerosol nasal o inhalation. Dichas composiciones se preparan de acuerdo con tecnicas bien conocidas en la tecnica de formulacion farmaceutica y pueden prepararse como soluciones en solution salina, empleando alcohol bencilico u otros conservantes adecuados, promotores de absorcion para potenciar la biodisponibilidad, fluorocarbonos, y/u otros agentes solubilizantes o dispersantes conocidos en la tecnica.The pharmaceutical compositions of this invention can be administered by nasal spray or inhalation. Such compositions are prepared in accordance with techniques well known in the art of pharmaceutical formulation and can be prepared as solutions in saline solution, using benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing agents or dispersants known in the art.

Puede administrarse una composicion que tiene el compuesto de las formulas de este documento y un agente adicional (por ejemplo, un agente terapeutico) usando un dispositivo implantable. Los dispositivos implantables y tecnologias relacionadas son conocidos en la tecnica y son utiles como sistemas de suministro cuando se desea un suministro continuo, o de liberation temporalizada de compuestos o composiciones definidas en este documento. Adicionalmente, el sistema de suministro de dispositivo implantable es util para abordar puntos especificos de suministro de compuesto o composicion (por ejemplo, sitios localizados, organos). Negrin et al., Biomaterials, 22(6):563 (2001). Tambien puede usarse en esta invencion la tecnologia de liberacion temporalizada que implica metodos alternativos de suministro. Por ejemplo, tambien pueden usarse formulaciones de liberacion temporalizada basadas en tecnologias polimericas, tecnicas de liberacion sostenida y tecnicas de encapsulation (por ejemplo, polimericas, liposomicas) para el suministro de los compuestos y composiciones definidos en este documento.A composition having the compound of the formulas herein and an additional agent (for example, a therapeutic agent) can be administered using an implantable device. Implantable devices and related technologies are known in the art and are useful as delivery systems when a continuous supply is desired, or for temporary release of compounds or compositions defined herein. Additionally, the implantable device supply system is useful for addressing specific points of supply of compound or composition (eg, localized sites, organs). Negrin et al., Biomaterials, 22 (6): 563 (2001). Also, in this invention, the technology of temporalized release that involves alternative methods of supply can be used. For example, time-release formulations based on polymer technologies, sustained release techniques and encapsulation techniques (eg, polymeric, liposomics) can also be used for the delivery of the compounds and compositions defined herein.

Tambien dentro de la invencion esta un parche para suministrar combinaciones quimioterapeuticas activas de este documento. Un parche incluye una capa de material (por ejemplo, polimerico, tela, gasa, venda) y el compuesto de las formulas de este documento como se define en este documento. Un lado de la capa de material puede tener una capa protectora adherida a la misma para resistir el paso de los compuestos o composiciones. El parche puede incluir adicionalmente un adhesivo para mantener el parche en su sitio en un sujeto. Un adhesivo es una composicion, incluyendo aquellas de origen natural o sintetico, que cuando se pone en contacto con la piel de un sujeto, se adhiere temporalmente a la piel. Puede resistente al agua. El adhesivo puede colocarse sobre el parche para mantenerlo en contacto con la piel del sujeto durante un periodo prolongado de tiempo. El adhesivo puede estar hecho de una fuerza adherente, o adhesiva, tal que mantenga el dispositivo en su sitio sometido a contacto accidental, sin embargo, tras un acto afirmativo (por ejemplo, desgarro, peladura, u otra retirada intencionada) el adhesivo ceda a la presion externa situada sobre el dispositivo o el propio adhesivo, y permita la rotura del contacto de adhesion. El adhesivo puede ser sensible a presion, es decir, puede permitir el posicionamiento del adhesivo (y elAlso within the invention is a patch to deliver active chemotherapeutic combinations of this document. A patch includes a layer of material (for example, polymeric, cloth, gauze, bandage) and the compound of the formulas in this document as defined in this document. One side of the material layer may have a protective layer adhered thereto to resist the passage of the compounds or compositions. The patch may additionally include an adhesive to keep the patch in place on a subject. An adhesive is a composition, including those of natural or synthetic origin, that when it comes in contact with the skin of a subject, temporarily adheres to the skin. It can waterproof. The adhesive can be placed on the patch to keep it in contact with the subject's skin for a prolonged period of time. The adhesive can be made of an adherent, or adhesive, force that keeps the device in its place subject to accidental contact, however, after an affirmative act (eg tearing, peeling, or other intentional removal) the adhesive yields to the external pressure placed on the device or the adhesive itself, and allow the adhesion contact to break. The adhesive can be pressure sensitive, that is, it can allow the positioning of the adhesive (and the

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dispositivo a adherir a la piel) contra la piel mediante la aplicacion de presion (por ejemplo, empuje, frotamiento) sobre el adhesivo o dispositivo.device to adhere to the skin) against the skin by applying pressure (for example, pushing, rubbing) on the adhesive or device.

Cuando las composiciones de esta invencion comprenden una combinacion de un compuesto de las formulas descritas en este documento y uno o mas agentes terapeuticos o profilacticos adicionales, tanto el compuesto como el agente adicional deben estar presentes a niveles de dosificacion entre aproximadamente el 1 al 100 %, y mas preferiblemente entre aproximadamente el 5 al 95 % de la dosificacion normalmente administrada en un regimen de monoterapia. Los agentes adicionales pueden administrarse por separado, como parte de un regimen de multiples dosis, de los compuestos de esta invencion. Como alternativa, los agentes pueden ser parte de una forma monodosis, mezclados juntos con los compuestos de esta invencion en una unica composicion.When the compositions of this invention comprise a combination of a compound of the formulas described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent must be present at dosage levels between about 1 to 100%. , and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen. Additional agents may be administered separately, as part of a multiple dose regimen, of the compounds of this invention. Alternatively, the agents can be part of a single dose form, mixed together with the compounds of this invention in a single composition.

La cita de una enumeracion de grupos quimicos en cualquier definition de una variable en el presente documento incluye definiciones de esa variable como cualquier grupo individual o combinacion de los grupos enumerados. La cita de una realizacion para una variable en el presente documento incluye esa realizacion como una realizacion individual o junto con cualesquiera otras realizaciones o porciones de las mismas.The citation of an enumeration of chemical groups in any definition of a variable in this document includes definitions of that variable as any individual group or combination of the groups listed. The citation of an embodiment for a variable in this document includes that embodiment as an individual embodiment or together with any other embodiments or portions thereof.

La invencion se describira adicionalmente en los siguientes ejemplos. Debe entenderse que estos ejemplos son para fines ilustrativos unicamente y no se interpretaran como limitantes de esta invencion de ningun modo.The invention will be further described in the following examples. It should be understood that these examples are for illustrative purposes only and will not be construed as limiting this invention in any way.

EjemplosExamples

El procedimiento general para la preparation de muchos ejemplos se muestra a continuation:The general procedure for the preparation of many examples is shown below:

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Etapa 1: Una mezcla de 5-fluoro-1,3-dihidroindol-2-ona (A2) (20 g, 132 mmol), acido 5-formil-2,4-dimetilpirrol-3- carboxilico (A1) (21,1 g, 126 mmol), pirrolidina (5 ml) y etanol absoluto (400 ml) se calentaron a reflujo durante 3 horas. Despues, la mezcla se enfrio a temperatura ambiente y el solido se recogio por filtracion y se lavo con etanol (100 ml). El solido se agito de nuevo en etanol (350 ml) a reflujo durante 0,5 h. La mezcla se enfrio a temperatura ambiente y el solido se recogio por filtracion, se lavo con etanol (100 ml) y se seco al vacio durante una noche para dar acido (Z)-5-((5-fluoro-2-oxoindolin-3-ilideno)metil)-2,4-dimetil-1H-pirrol-3-carboxnico (A3) (35,3 g, 93 %) en forma de un solido de color naranja. CL-EM observado [M-H]+: 299,2.Stage 1: A mixture of 5-fluoro-1,3-dihydroindole-2-one (A2) (20 g, 132 mmol), 5-formyl-2,4-dimethylpyrrol-3- carboxylic acid (A1) (21, 1 g, 126 mmol), pyrrolidine (5 ml) and absolute ethanol (400 ml) were heated at reflux for 3 hours. Then, the mixture was cooled to room temperature and the solid was collected by filtration and washed with ethanol (100 ml). The solid was stirred again in ethanol (350 ml) at reflux for 0.5 h. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol (100 ml) and dried in vacuo overnight to give acid (Z) -5- ((5-fluoro-2-oxoindolin- 3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxylic acid (A3) (35.3 g, 93%) as an orange solid. LC-MS observed [M-H] +: 299.2.

Etapa 2: Se suspendio acido (Z)-5-((5-fluoro-2-oxoindolin-3-ilideno)metil)-2,4-dimetil-1H-pirrol-3-carboxnico (A3) (5 g, 16,7 mmol) en DMF (25 ml) con agitation durante 5 min. Despues, se anadio DIEA (4,4 ml, 25 mmol) y la mezcla se agito durante 10 min. Se anadio HATU (6,32 g, 16,6 mmol) y la mezcla de reaction se agito a temperatura ambiente durante varias horas. Se uso analisis por CL/EM para detectar la finalization de la reaccion. La mayor parte de la DMF se evaporo al vacio y el residuo se suspendio en ACN y se agito durante 30 min mas. El solido se recogio por filtracion, se lavo con ACN y se seco al vacio para proporcionar 5-((5-fluoro-2-oxoindolin-3-ilideno)metil)-2,4-dimetil- 1 H-pirrol-3-carboxilato de (Z)-3H-[1,2,3] triazolo[4,5-b]piridin-3-ilo (A4) (5,36 g, 77 %). CL-ESIMS observado [M-H]+: 417,3.Stage 2: Acid (Z) -5 - ((5-fluoro-2-oxoindolin-3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxylic acid (A3) (5 g, 16 , 7 mmol) in DMF (25 ml) with stirring for 5 min. Then, DIEA (4.4 ml, 25 mmol) was added and the mixture was stirred for 10 min. HATU (6.32 g, 16.6 mmol) was added and the reaction mixture was stirred at room temperature for several hours. LC / MS analysis was used to detect the completion of the reaction. Most of the DMF was evaporated in vacuo and the residue was suspended in ACN and stirred for an additional 30 min. The solid was collected by filtration, washed with ACN and dried in vacuo to provide 5 - ((5-fluoro-2-oxoindolin-3-ylidene) methyl) -2,4-dimethyl- 1 H -pyrrole-3- (Z) -3H- [1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) carboxylate (5.36 g, 77%). CL-ESIMS observed [M-H] +: 417.3.

Etapa 3: A la solution de 5-((5-fluoro-2-oxoindolin -3-ilideno) metil)-2,4- dimetil-1H-pirrol-3-carboxilato de (Z)-3H-Step 3: To the solution of 5 - ((5-fluoro-2-oxoindolin -3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxylate of (Z) -3H-

[1,2,3]triazolo[4,5-b]piridin-3-ilo (A4) (1,0 equiv.) en una solucion de DMF se le anadio la amina apropiada (1,2 equiv.) y DIEA (2,0 equiv.). La mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico detection por CL/eM para determinar la finalizacion de la reaccion. Despues de la elimination de la mayor parte de la DMF al vacio la mezcla se precipito con dietilamina al 5 %/metanol (25 ml) con agitacion. El solido se recogio por filtracion, se lavo con metanol (5 ml) varias veces, se seco a alto vacio para proporcionar el compuesto final (rendimiento del 40-85 %).[1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) (1.0 equiv.) In a DMF solution the appropriate amine (1.2 equiv.) And DIEA were added (2.0 equiv.). The reaction mixture was stirred at room temperature for several hours. CL / eM detection was applied to determine the completion of the reaction. After elimination of most of the DMF in vacuo the mixture was precipitated with 5% diethylamine / methanol (25 ml) with stirring. The solid was collected by filtration, washed with methanol (5 ml) several times, dried under high vacuum to provide the final compound (yield 40-85%).

Ejemplo 1: Preparacion de (4-hidroxi-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 1: Preparation of (4-hydroxy-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1H- pyrrole-3-carboxy

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Siguiendo el procedimiento general, se obtuvo un solido de color naranja (162 mg, rendimiento del 86 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,64(s, 1H), 10,86(s, 1H), 7,72-7,77(dd, 1H), 7,70(s, 1H), 7,45-7,47(d, 1H), 6,81-6,95(m, 2H), 4,52-4,53(d, 1H), 3,66-3,68(m, 1H), 3,36-3,39(m, 1H), 2,38-2,40(ds, 6H), 1,82-1,86(d, 4H), 1,23-1,34(m, 4H). CL/EM: 398,3 [M+H]+.Following the general procedure, an orange solid (162 mg, 86% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): 5 = 13.64 (s, 1H), 10.86 (s, 1H), 7.72-7.77 (dd, 1H), 7.70 (s, 1H), 7.45-7.47 (d, 1H), 6.81-6.95 (m, 2H), 4.52-4.53 (d, 1H), 3.66-3.68 ( m, 1H), 3.36-3.39 (m, 1H), 2.38-2.40 (ds, 6H), 1.82-1.86 (d, 4H), 1.23-1, 34 (m, 4H). LC / MS: 398.3 [M + H] +.

Ejemplo 2: Preparacion de (1-acetil-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 2: Preparation of (1-acetyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4- dimethyl-1H-pyrrole-3-carboxyNico

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Siguiendo el procedimiento general, se obtuvo un solido de color naranja (174 mg, rendimiento del 83 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,88(s, 1H), 7,74-7,78(dd, 1H), 7,71(s, 1H), 7,59-7,62(d, 1H), 6,81-6,96(m, 2H), 4,23-4,27(d, 1H), 3,96-3,99(m, 1H), 3,76-3,81(m, 1H), 3,11-3,19(m, 1H), 2,70-2,74(m, 1H), 2,39-2,41(ds, 6H), 2,00(s, 3H), 1,77-1,89(m, 2H), 1,31-1,47(m, 2H). CL/EM: 423,4 [M-H]+.Following the general procedure, an orange solid (174 mg, 83% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.88 (s, 1H), 7.74-7.78 (dd, 1H), 7.71 (s, 1H), 7.59-7.62 (d, 1H), 6.81-6.96 (m, 2H), 4.23-4.27 (d, 1H), 3.96-3.99 ( m, 1H), 3.76-3.81 (m, 1H), 3.11-3.19 (m, 1H), 2.70-2.74 (m, 1H), 2.39-2, 41 (ds, 6H), 2.00 (s, 3H), 1.77-1.89 (m, 2H), 1.31-1.47 (m, 2H). LC / MS: 423.4 [M-H] +.

Ejemplo 3: Preparacion de (1-metanosulfonil-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxllicoExample 3: Preparation of (1-methanesulfonyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4- dimethyl-1H-pyrrole-3-carboxylic

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Siguiendo el procedimiento general, se obtuvo un solido de color naranja (171 mg, rendimiento del 77 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,90(s, 1H), 7,67-7,79(m, 3H), 6,83-6,93(m, 2H), 3,89-3,91 (m, 1H), 3,51- 3,55(d, 2H), 2,85-2,91(m, 5H), 2,27-2,41(ds, 6H), 1,90-1,95(d, 2H), 1,58-1,61(m, 2H). CL/EM: 459,4 [M-H]+.Following the general procedure, an orange solid (171 mg, 77% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.90 (s, 1H), 7.67-7.79 (m, 3H), 6.83-6, 93 (m, 2H), 3.89-3.91 (m, 1H), 3.51-3.55 (d, 2H), 2.85-2.91 (m, 5H), 2.27- 2.41 (ds, 6H), 1.90-1.95 (d, 2H), 1.58-1.61 (m, 2H). LC / MS: 459.4 [M-H] +.

Ejemplo 4: Preparacion de (4-amino-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxllicoExample 4: Preparation of (4-amino-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1H- pyrrole-3-carboxylic

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Siguiendo el procedimiento general, se obtuvo un solido de color naranja (121 mg, rendimiento del 63 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,65(s, 1H), 7,70-7,77(m, 2H), 7,44-7,47(d, 1H), 6,81-6,92(m, 2H), 3,62-3,71(m, 1H), 2,38-2,40(ds, 6H), 1,76-1,84(m, 4H), 1,10-1,32(m, 5H). CL/EM: 397,2 [M+H]+.Following the general procedure, an orange solid (121 mg, 63% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): 5 = 13.65 (s, 1H), 7.70-7.77 (m, 2H), 7.44-7.47 (d, 1H), 6, 81-6.92 (m, 2H), 3.62-3.71 (m, 1H), 2.38-2.40 (ds, 6H), 1.76-1.84 (m, 4H), 1.10-1.32 (m, 5H). LC / MS: 397.2 [M + H] +.

Ejemplo 5: Preparacion de N-(2H-3,4,5,6-tetrahidropiran-4-N){5-[(5-fluoro-2-oxo(1H-benzo[d]azolm-3-Example 5: Preparation of N- (2H-3,4,5,6-tetrahydropyran-4-N) {5 - [(5-fluoro-2-oxo (1H-benzo [d] azolm-3-

iliden))metil]-2,4-dimetilpirrol-3-il}carboxamidailiden)) methyl] -2,4-dimethylpyrrol-3-yl} carboxamide

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Etapa 1: Una mezcla de acido 5-formil-2,4-dimetilpirrol-3-carboxilico (A1) (1 g, 6,0 mmol) en 25 ml de DMF anhidra se agito a temperatura ambiente mientras que se anadieron HOBt (1,216 g, 9,0 mmol), EDCI (1,726 g, 9,0 mmol), TEA (3,4 ml, 24 mmol) y 2H-3,4,5,6-tetrahidropiran-4-ilamina (5a) (0,99 g, 7,2 mmol). La mezcla resultante se agito durante 20 h a temperatura ambiente. Despues, la mezcla de reaccion se diluyo con 3 ml cada vez de H2O y salmuera y una solucion saturada de bicarbonato sodico. El pH se ajusto a mas de 10 con una solucion acuosa 10 N de NaOH. La mezcla se extrajo tres veces con 10 ml de DCM que contenia metanol al 10 %. Los extractos se combinaron, se secaron sobre MgSO4 anhidro y se evaporaron al vacio. El residuo se trituro con un disolvente mixto de AE:MeOH (5:1, 10 ml). El solido resultante se filtro y se seco para proporcionar el compuesto N-(2H-3,4,5,6- tetrahidropiran-4-il) (5-formil-2,4-dimetilpirrol-3-il)carboxamida (5b) en forma de un solido de color blanco. (475 mg, 32 %). CL-EM: 249,3 [M-H]+.Step 1: A mixture of 5-formyl-2,4-dimethylpyrrol-3-carboxylic acid (A1) (1 g, 6.0 mmol) in 25 ml of anhydrous DMF was stirred at room temperature while HOBt (1,216 were added g, 9.0 mmol), EDCI (1,726 g, 9.0 mmol), TEA (3.4 ml, 24 mmol) and 2H-3,4,5,6-tetrahydropyran-4-ylamine (5a) (0 , 99 g, 7.2 mmol). The resulting mixture was stirred for 20 h at room temperature. Then, the reaction mixture was diluted with 3 ml each of H2O and brine and a saturated sodium bicarbonate solution. The pH was adjusted to more than 10 with a 10 N aqueous solution of NaOH. The mixture was extracted three times with 10 ml of DCM containing 10% methanol. The extracts were combined, dried over anhydrous MgSO4 and evaporated in vacuo. The residue is triturated with a mixed solvent of AE: MeOH (5: 1, 10 ml). The resulting solid was filtered and dried to provide compound N- (2H-3,4,5,6-tetrahydropyran-4-yl) (5-formyl-2,4-dimethylpyrrol-3-yl) carboxamide (5b) in the form of a white solid. (475 mg, 32%). LC-MS: 249.3 [M-H] +.

Etapa 2: Una mezcla de 2N-(2H-3,4,5,6-tetrahidropiran-4-il)(5-formil-2,4-dimetilpirrol-3-il)-carboxamida (5b) (200 mg, 0,8 mmol), 5-fluoroindolin-2-ona (A2) (126 mg, 0,84 mmol) y pirrolidina (dos gotas) en 10 ml de etanol se calentaron a reflujo durante 3 h. La mezcla se enfrio a temperatura ambiente y el solido se recogio por filtracion y se lavo con etanol. El solido obtenido se agito de nuevo en etanol (10 ml) a reflujo durante 0,5 h. La mezcla se enfrio a temperatura ambiente y el solido se recogio por filtracion, se lavo con etanol y se seco al vacio para dar el compuesto del titulo (80 mg, rendimiento del 26 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,87(s, 1H), 7,74-7,78(dd, 1H), 7,71(s, 1H), 7,60-6,63 (d, 1H), 6,82-6,96 (m, 2H), 3,83- 3,98(m, 3H), 3,38-3,42(m, 2H), 2,40-2,42(ds, 6H), 1,76-1,81 (dd, 1H), 1,56-1,59 (m, 2H). CL/EM: 382,4 [M-H]+.Stage 2: A mixture of 2N- (2H-3,4,5,6-tetrahydropyran-4-yl) (5-formyl-2,4-dimethylpyrrol-3-yl) -carboxamide (5b) (200 mg, 0 , 8 mmol), 5-fluoroindolin-2-one (A2) (126 mg, 0.84 mmol) and pyrrolidine (two drops) in 10 ml of ethanol were heated at reflux for 3 h. The mixture was cooled to room temperature and the solid was collected by filtration and washed with ethanol. The solid obtained was stirred again in ethanol (10 ml) at reflux for 0.5 h. The mixture was cooled to room temperature and the solid was collected by filtration, washed with ethanol and dried in vacuo to give the title compound (80 mg, 26% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.87 (s, 1H), 7.74-7.78 (dd, 1H), 7.71 (s, 1H), 7.60-6.63 (d, 1H), 6.82-6.96 (m, 2H), 3.83-3.98 (m, 3H), 3.38-3.42 ( m, 2H), 2.40-2.42 (ds, 6H), 1.76-1.81 (dd, 1H), 1.56-1.59 (m, 2H). LC / MS: 382.4 [M-H] +.

Ejemplo 6: Preparacion de piperidin-4-ilamida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-Example 6: Preparation of piperidin-4-ylamide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -

2,4-dimetil-1H-pirrol-3-carboxilico2,4-dimethyl-1H-pyrrole-3-carboxylic

imagen10image10

Etapa 1: Se anadio Cbz-Cl (0,938 g, 5,5 mmol) a la solucion del compuesto 6a (1 g, 5 mmol) y TEA (0,823 ml, 6 mmol) en 30 ml de DMF. La mezcla resultante se agito a temperatura ambiente durante 45 min, y despues se anadieron 30 ml de H2O. La mezcla se extrajo por AE (50 ml x 3). Los extractos organicos combinados se secaron sobre MgSO4 anhidro, se filtraron, y el filtrado se evaporo a presion reducida para dar un residuo, que se purifico por cromatografia en columna (AE:PE = 1:10) para proporcionar el compuesto 6b (1,46 g, 87 %) en forma de un solido de color blanco, que se uso directamente en la siguiente etapa.Step 1: Cbz-Cl (0.938 g, 5.5 mmol) was added to the solution of compound 6a (1 g, 5 mmol) and TEA (0.823 ml, 6 mmol) in 30 ml of DMF. The resulting mixture was stirred at room temperature for 45 min, and then 30 ml of H2O was added. The mixture was extracted by EA (50 ml x 3). The combined organic extracts were dried over anhydrous MgSO4, filtered, and the filtrate was evaporated under reduced pressure to give a residue, which was purified by column chromatography (EA: PE = 1:10) to provide compound 6b (1, 46 g, 87%) in the form of a white solid, which was used directly in the next stage.

Etapa 2: El compuesto 6b (1,46 g, 0,44 mmol) se disolvio en 50 ml de DCM y se anadieron 5,76 ml de TFA. La solucion resultante se agito a temperatura ambiente durante 2 h y se evaporo a sequedad para proporcionar el compuesto 6c (1,84 g, 99 %) que se uso directamente en la siguiente etapa.Step 2: Compound 6b (1.46 g, 0.44 mmol) was dissolved in 50 ml of DCM and 5.76 ml of TFA was added. The resulting solution was stirred at room temperature for 2 h and evaporated to dryness to provide compound 6c (1.84 g, 99%) which was used directly in the next step.

Etapas 3 y 4: A la solucion de 5-[(5-fluoro-2-oxoindolin-3-ilideno)metil]-2,4-dimetil-1H-pirrol-3-carboxilato de (Z)-3H-Stages 3 and 4: To the solution of 5 - [(5-fluoro-2-oxoindolin-3-ylidene) methyl] -2,4-dimethyl-1H-pyrrole-3-carboxylate of (Z) -3H-

[1,2,3]triazolo[4,5-b]piridin-3-ilo (A4) (0,2 g, 0,48 mmol) en 25 ml de una solucion de DMF se le anadio el compuesto 6c (0,268 g, 0,58 mmol). La mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. A la mezcla se le anadieron 200 mg de Pd al 5 %/C seguido de 25 ml de MeOH. La mezcla se agito en una atmosfera de H2 durante 30 min y se filtro. El filtrado se evaporo a presion reducida y el residuo se trituro con dietilamina al 5 %/metanol (25 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol (5 ml x 2) y se seco al vacio para proporcionar el compuesto del titulo (80 mg, rendimiento del 43,7 %) en forma de un solido de color naranja. rMn 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,89(s, 1H), 7,67-7,78(m, 3H), 6,82-6,96(m, 2H), 3,87-3,92(m,1H), 3,06-3,09(d,2H), 2,72-2,79(t,2H), 2,392,41 (ds, 6H), 1,84-1,89 (d,6H), 1,46-1,57(m, 2H). CL/EM: 383,1 [M+H]+.[1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) (0.2 g, 0.48 mmol) in 25 ml of a DMF solution was added compound 6c (0.268 g, 0.58 mmol). The reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. To the mixture was added 200 mg of 5% Pd / C followed by 25 ml of MeOH. The mixture was stirred in an H2 atmosphere for 30 min and filtered. The filtrate was evaporated under reduced pressure and the residue was triturated with 5% diethylamine / methanol (25 ml) with sonication. The solid was collected by filtration, washed with methanol (5 ml x 2) and dried in vacuo to provide the title compound (80 mg, 43.7% yield) as an orange solid. rMn 1H (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.89 (s, 1H), 7.67-7.78 (m, 3H), 6.82-6, 96 (m, 2H), 3.87-3.92 (m, 1H), 3.06-3.09 (d, 2H), 2.72-2.79 (t, 2H), 2,392.41 ( ds, 6H), 1.84-1.89 (d, 6H), 1.46-1.57 (m, 2H). LC / MS: 383.1 [M + H] +.

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Ejemplo 7: Preparacion de (4-oxo-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 7: Preparation of (4-oxo-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1H- pyrrole-3-carboxylic

imagen11image11

Etapa 1: El compuesto 7a (2,5 g, 11,74 mmol) se disolvio en 40 ml de DCM. Se anadieron lentamente 15,3 ml de TFA. La mezcla resultante se agito a temperatura ambiente durante 2 h, y despues se evaporo a sequedad al vado para proporcionar el compuesto en bruto 7b (2,60 g, 98 %), que se uso directamente en la siguiente etapa.Step 1: Compound 7a (2.5 g, 11.74 mmol) was dissolved in 40 ml of DCM. 15.3 ml of TFA were added slowly. The resulting mixture was stirred at room temperature for 2 h, and then evaporated to dryness in vacuo to provide the crude compound 7b (2.60 g, 98%), which was used directly in the next step.

Etapa 2: A la solucion de 5-[(5-fluoro -2-oxoindolin-3-ilideno)metil]-2,4-dimetil-1H-pirrol-3-carboxilato de (Z)-3H-Step 2: To the solution of 5 - [(5-fluoro -2-oxoindolin-3-ylidene) methyl] -2,4-dimethyl-1H-pyrrole-3-carboxylate of (Z) -3H-

[1,2,3]triazolo[4,5-b]piridin-3-ilo (A4) (0,2 g, 0,48 mmol) en 25 ml de una solucion de DMF se le anadio el compuesto 7b (0,13 g, 0,58 mmol), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (25 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol (5 ml x 2) y se seco al vado para proporcionar el compuesto del tftulo (50 mg, rendimiento del 26 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,89(s, 1H), 7,70-7,78(m, 3H), 6,82-6,93(m, 2H), 4,21-4,28(m,1H), 2,41-2,49(m, 8H), 2,28-2,31 (m,2H), 2,07-2,13(m,2H), 1,76-1,80(m, 2H). CL/EM: 394,3 [M-H]+.[1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) (0.2 g, 0.48 mmol) in 25 ml of a DMF solution was added compound 7b (0 , 13 g, 0.58 mmol), and the reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (25 ml) with sonication. The solid was collected by filtration, washed with methanol (5 ml x 2) and dried in vacuo to provide the title compound (50 mg, 26% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.89 (s, 1H), 7.70-7.78 (m, 3H), 6.82-6, 93 (m, 2H), 4.21-4.28 (m, 1H), 2.41-2.49 (m, 8H), 2.28-2.31 (m, 2H), 2.07- 2.13 (m, 2H), 1.76-1.80 (m, 2H). LC / MS: 394.3 [M-H] +.

Ejemplo 8: Preparacion de ((S)-1-acetil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 8: Preparation of ((S) -1-acetyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxylic

imagen12image12

Preparacion de aminas para los ejemplos 8 y 9:Preparation of amines for examples 8 and 9:

imagen13image13

BocNHBocNH

-Oh  -Oh
^ 8b 8c  ^ 8b 8c

•TFA ✓  • TFA ✓

8a  8a
BocNH5 ’o  BocNH5 ’or

9b 9c  9b 9c

Etapa 1a: El compuesto 8a (0,5 g, 2,7 mmol) y TEA (0,326 g, 3,2 mmol) se combinaron en 5 ml de DCM. Se anadio gota a gota cloruro de acetilo (0,253 g, 3,2 mmol). La mezcla resultante se agito a temperatura ambiente durante 4 h y se evaporo a presion reducida. El residuo se disolvio en AE y se lavo con una solucion acuosa al 5 % de NaHCO3 y salmuera. La capa organica se seco sobre MgSO4 anhidro y se evaporo para proporcionar el compuesto en bruto 8b (0,548 g, 90 %), que se uso directamente en la siguiente etapa.Step 1a: Compound 8a (0.5 g, 2.7 mmol) and TEA (0.326 g, 3.2 mmol) were combined in 5 ml of DCM. Acetyl chloride (0.253 g, 3.2 mmol) was added dropwise. The resulting mixture was stirred at room temperature for 4 h and evaporated under reduced pressure. The residue was dissolved in EA and washed with a 5% aqueous solution of NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to provide the crude compound 8b (0.548 g, 90%), which was used directly in the next step.

Etapa 1b: A una solucion enfriada con un bano de hielo del compuesto en bruto 8a (0,5 g, 2,7 mmol) y DIEA (1,6 g, 12,3 mmol) en 20 ml de THF se le anadio gota a gota cloruro de mesilo (0,54 g, 4,7 mmol). Despues, la mezcla se agito a temperatura ambiente durante aproximadamente 1 h, se vertio en agua y se extrajo con DCM. La fase organica combinada se lavo con una solucion ac. al 5 % de NaHCO3, se seco sobre MgSO4 anhidro, se filtro y elStep 1b: To a solution cooled with an ice bath of the crude compound 8a (0.5 g, 2.7 mmol) and DIEA (1.6 g, 12.3 mmol) in 20 ml of THF was added dropwise dropwise mesyl chloride (0.54 g, 4.7 mmol). Then, the mixture was stirred at room temperature for about 1 h, poured into water and extracted with DCM. The combined organic phase was washed with an ac solution. 5% NaHCO3, dried over anhydrous MgSO4, filtered and the

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filtrado se evaporo a presion reducida para dar el compuesto en bruto 9b (0,654 g, 92 %), que se uso directamente en la siguiente etapa.The filtrate was evaporated under reduced pressure to give the crude compound 9b (0.654 g, 92%), which was used directly in the next step.

Etapa 2: El compuesto 8b o 9b (1,0 equiv.) se disolvio en DCM. Se anadio lentamente TFA (10 equiv.). La mezcla resultante se agito a temperatura ambiente durante 2 h y se evaporo a sequedad al vado para proporcionar el compuesto 8c o 9c.Stage 2: Compound 8b or 9b (1.0 equiv.) Was dissolved in DCM. TFA (10 equiv.) Was added slowly. The resulting mixture was stirred at room temperature for 2 h and evaporated to dryness in vacuo to provide compound 8c or 9c.

Etapa 3: A la solucion de 5-((5-fluoro-2-oxoindolin-3-ilideno)metil)-2,4-dimetil-1H-pirrol-3-carboxilato de (Z)-3H-Step 3: To the solution of 5 - ((5-fluoro-2-oxoindolin-3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxylate of (Z) -3H-

[1,2,3]triazolo[4,5-b]piridin-3-ilo (A4) (1,0 equiv.) y DIEA (2,0 equiv.) en una solucion de DMF se le anadio el compuesto 8c (1,2 equiv.), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol con sonicacion. El solido se recogio por filtracion, se lavo dos veces con metanol y se seco a alto vacio para proporcionar el compuesto del titulo (136 mg, rendimiento del 66 %) en forma de un solido de color naranja. rMn 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,89(s, 1H), 7,72-7,92(m, 3H), 6,82-6,96(m, 2H), 4,34-4,48(m,1H), 3,25-3,75(m, 4H), 2,39-2,42(ds,6H), 1,86-2,20(m, 6H). CL/EM: 409,3 [M-H]+.[1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) (1.0 equiv.) And DIEA (2.0 equiv.) In a DMF solution compound 8c was added (1.2 equiv.), And the reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol with sonication. The solid was collected by filtration, washed twice with methanol and dried at high vacuum to provide the title compound (136 mg, 66% yield) as an orange solid. rMn 1H (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.89 (s, 1H), 7.72-7.92 (m, 3H), 6.82-6, 96 (m, 2H), 4.34-4.48 (m, 1H), 3.25-3.75 (m, 4H), 2.39-2.42 (ds, 6H), 1.86- 2.20 (m, 6H). LC / MS: 409.3 [M-H] +.

Ejemplo 9: Preparacion de ((S)-1-metanosulfonil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxflicoExample 9: Preparation of ((S) -1-methanesulfonyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxylic acid

imagen14image14

A la solucion de 5-((5-fluoro-2-oxoindolin-3-ilideno)metil)-2,4-dimetil-1H-pirrol-3-carboxilato de (Z)-3H-To the solution of 5 - ((5-fluoro-2-oxoindolin-3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxylate of (Z) -3H-

[1,2,3]triazolo[4,5-b]piridin-3-ilo (A4) (1,0 equiv.) y DIEA (2,0 equiv.) en una solucion de DMF se le anadio el compuesto 9c (1,2 equiv.), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol con sonicacion. El solido se recogio por filtracion, se lavo dos veces con metanol y se seco a alto vacio para proporcionar el compuesto del titulo (129 mg, rendimiento del 61 %) en forma de un solido de color naranja. rMn 1H (300 MHz, DMSO-d6): 5 = 13,70(s, 1H), 10,90(s, 1H), 7,72-7,90(m, 3H), 6,82-6,96(m, 2H), 4,42-4,48(m,1H), 3,53-3,58(m, 1H), 3,36-3,42(m, 1H), 3,13-3,18(m, 1H), 2,93(s, 3H), 2,41- 2,43(ds, 6H), 1,90-2,18(m,3H). CL/EM: 445,4 [M-H]+.[1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) (1.0 equiv.) And DIEA (2.0 equiv.) In a DMF solution compound 9c was added (1.2 equiv.), And the reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol with sonication. The solid was collected by filtration, washed twice with methanol and dried at high vacuum to provide the title compound (129 mg, 61% yield) as an orange solid. rMn 1H (300 MHz, DMSO-d6): 5 = 13.70 (s, 1H), 10.90 (s, 1H), 7.72-7.90 (m, 3H), 6.82-6, 96 (m, 2H), 4.42-4.48 (m, 1H), 3.53-3.58 (m, 1H), 3.36-3.42 (m, 1H), 3.13- 3.18 (m, 1H), 2.93 (s, 3H), 2.41-2.43 (ds, 6H), 1.90-2.18 (m, 3H). LC / MS: 445.4 [M-H] +.

Ejemplo 10: Preparacion de (1,1-dioxo-tetrahidro-tiofen-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 10: Preparation of (1,1-dioxo-tetrahydro-thiophene-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxMico

imagen15image15

Preparacion de 1,1-Dioxo-tetrahidro-tiofen-3-ilamina:Preparation of 1,1-Dioxo-tetrahydro-thiophene-3-ylamine:

imagen16image16

10a10th

H,NH, N

PP

.-.O.-.OR

10b10b

Una solucion del compuesto 10a (0,5 g, 4,2 mmol) en 10 ml de NH4OH al 26 % se calento en un tubo cerrado hermeticamente a 80 °C durante 4 h. La mezcla se concentro a presion reducida para dar un aceite de color amarillo que se disolvio en 3 ml de EtOH y se trato con 1 ml de HCl concentrado. La mezcla se agito durante 0,5 h y se anadio eter etilico para precipitar el clorhidrato cristalino. El solido se recogio por filtracion, se lavo con eter y se seco al vacio para proporcionar el compuesto 10b (0,533 g, 74 %).A solution of compound 10a (0.5 g, 4.2 mmol) in 10 ml of 26% NH4OH was heated in a tightly sealed tube at 80 ° C for 4 h. The mixture was concentrated under reduced pressure to give a yellow oil that was dissolved in 3 ml of EtOH and treated with 1 ml of concentrated HCl. The mixture was stirred for 0.5 h and ethyl ether was added to precipitate the crystalline hydrochloride. The solid was collected by filtration, washed with ether and dried in vacuo to provide compound 10b (0.533 g, 74%).

A la solucion de 5-[(5-fluoro-2-oxoindolin-3-ilideno)metil]-2,4-dimetil-1H-pirrol-3-carboxilato de (Z)-3H-To the solution of 5 - [(5-fluoro-2-oxoindolin-3-ylidene) methyl] -2,4-dimethyl-1H-pyrrole-3-carboxylate of (Z) -3H-

[1,2,3]triazolo[4,5-b]piridin-3-ilo (A4) (0,207 g, 0,5 mmol) y DlEA (0,296 g, 2,0 equiv.) en 25 ml de una solucion de DMF se le anadio el compuesto 10b (0,162 g, 0,94 mmol), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml) con sonicacion. El solido se[1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) (0.207 g, 0.5 mmol) and DlEA (0.296 g, 2.0 equiv.) In 25 ml of a solution of DMF compound 10b (0.162 g, 0.94 mmol) was added, and the reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml) with sonication. The solid is

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recogio por filtracion, se lavo dos veces con metanol (5 ml) y se seco al vado para proporcionar el compuesto del titulo en forma de un solido de color naranja (181 mg, rendimiento del 88 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,91 (s, 1H), 7,97-7,80(d, 1H), 7,73-7,70(m, 2H), 6,82-6,97(m, 2H),4,63-4,65(m, 1H), 3,44-3,51(m, 1H), 3,18-3,29(m, 1H), 3,03-3,10(m, 1H), 2,42-2,50(m, 8H), 2,16-2,23(d,6H). CL/EM: 416,2 [M-H]+.collected by filtration, washed twice with methanol (5 ml) and dried in vacuo to provide the title compound as an orange solid (181 mg, 88% yield). 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.91 (s, 1H), 7.97-7.80 (d, 1H), 7.73-7, 70 (m, 2H), 6.82-6.97 (m, 2H), 4.63-4.65 (m, 1H), 3.44-3.51 (m, 1H), 3.18- 3.29 (m, 1H), 3.03-3.10 (m, 1H), 2.42-2.50 (m, 8H), 2.16-2.23 (d, 6H). LC / MS: 416.2 [M-H] +.

Ejemplo 11: Preparacion de ((1S,2S)-2-hidroxiciclopentil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol- (3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 11: Preparation of ((1S, 2S) -2-hydroxycyclopentyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4- dimethyl-1H-pyrrole-3-carboxy

imagen17image17

Siguiendo el procedimiento general, se obtuvo un solido de color naranja (85 mg, rendimiento del 93 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,88(s, 1H), 7,52-7,78(m, 3H), 6,82-6,96(m, 2H), 4,76-4,77(d, 1H), 3,92- 3,97(m, 2H), 2,39-2,42(ds,6H), 1,96-2,01 (m, 1H), 1,80-1,84(m,1H), 1,60-1,69(m, 1H). CL/EM: 384,2 [M+H]+.Following the general procedure, an orange solid (85 mg, 93% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.88 (s, 1H), 7.52-7.78 (m, 3H), 6.82-6, 96 (m, 2H), 4.76-4.77 (d, 1H), 3.92-3.97 (m, 2H), 2.39-2.42 (ds, 6H), 1.96- 2.01 (m, 1H), 1.80-1.84 (m, 1H), 1.60-1.69 (m, 1H). LC / MS: 384.2 [M + H] +.

Ejemplo 12: Preparacion de ((1S,2R)-2-hidroxi-ciclopentil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol- (3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 12: Preparation of ((1S, 2R) -2-hydroxy-cyclopentyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2, 4-dimethyl-1H-pyrrole-3-carboxyNico

imagen18image18

Siguiendo el procedimiento general, se obtuvo un solido de color naranja (75 mg, rendimiento del 82 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,90(s, 1H), 7,72-7,79(m, 2H), 6,82-7,01 (m, 3H), 4,81-4,83(d, 1H), 4,02- 4,04(d, 2H), 2,44-2,47(ds,6H), 1,47-1,90(m, 6H). CL/EM: 384,1 [M+H]+.Following the general procedure, an orange solid (75 mg, 82% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.90 (s, 1H), 7.72-7.79 (m, 2H), 6.82-7, 01 (m, 3H), 4.81-4.83 (d, 1H), 4.02-4.04 (d, 2H), 2.44-2.47 (ds, 6H), 1.47- 1.90 (m, 6H). LC / MS: 384.1 [M + H] +.

Ejemplo 13: Preparacion de (1-pirimidin-2-il-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol- (3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxflicoExample 13: Preparation of (1-pyrimidin-2-yl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxylic acid

imagen19image19

Preparacion de amina:Amine Preparation:

BocNH-^\lH +BocNH - ^ \ lH +

6a 13a 13b6a 13a 13b

Etapa 1: Una mezcla del compuesto 6a (0,5 g, 2,5 mmol), 2-cloropirimidina(0,86 g, 7,5 mmol) y K2CO3 (1,725 g, 12,5 mmol) en 10 ml de 1,4-dioxano se calento a reflujo durante 48 h, se enfrio a temperatura ambiente y se filtro. El filtrado se evaporo a presion reducida y el residuo se purifico por cromatografia en columna (AE:PE = 1:4) para proporcionar el compuesto 13a (0,61 g, 88 %).Step 1: A mixture of compound 6a (0.5 g, 2.5 mmol), 2-chloropyrimidine (0.86 g, 7.5 mmol) and K2CO3 (1.725 g, 12.5 mmol) in 10 ml of 1 , 4-dioxane was heated at reflux for 48 h, cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by column chromatography (EA: PE = 1: 4) to give compound 13a (0.61 g, 88%).

Etapa 2: El compuesto 13a (0,61 g, 2,2 mmol) se disolvio en 10 ml de DCM y se anadieron 3 ml de TFA. La mezcla se agito a temperatura ambiente durante 2 h y se evaporo a sequedad a presion reducida para dar el compuesto en bruto 13b (0,87 g, 98 %).Step 2: Compound 13a (0.61 g, 2.2 mmol) was dissolved in 10 ml of DCM and 3 ml of TFA was added. The mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure to give the crude compound 13b (0.87 g, 98%).

A la solucion de 5-((5-fluoro-2-oxoindolin-3-ilideno)metil)-2,4-dimetil-1H-pirrol-3-carboxilato de (Z)-3H-To the solution of 5 - ((5-fluoro-2-oxoindolin-3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxylate of (Z) -3H-

[1,2,3]triazolo[4,5-b]piridin-3-ilo (A4) (0,207 g, 0,5 mmol) y DIEA (0,15 g, 2,0 equiv.) en 25 ml de una solucion de DMF se le anadio el compuesto 13b (0,235 g, 0,58 mmol), y la mezcla de reaccion se agito a temperatura ambiente[1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) (0.207 g, 0.5 mmol) and DIEA (0.15 g, 2.0 equiv.) In 25 ml of a solution of DMF was added compound 13b (0.235 g, 0.58 mmol), and the reaction mixture was stirred at room temperature

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durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol (5 ml x 2) y se seco al vado para proporcionar el compuesto del tftulo (189 mg, 82 %) en forma de un solido de color naranja. RMN 1H (300 mHz, DMSO-d6): 5 = 13,66(s, 1H), 10,87(s, 1H), 8,34-8,36(d, 2H), 7,71-7,77(m, 2H), 7,56-7,59(d, 1H), 6,82-6,95(m, 2H), 6,58-6,61(t,1H), 4,56-4,60(d, 2H), 4,04- 4,10(m, 1H), 3,06-3,13(m, 2H), 2,40-2,42(ds, 6H), 1,86-1,91 (d, 2H), 1,40-1,52(m, 2H). CL/EM: 459,4 [M-H]+.for several hours CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml) with sonication. The solid was collected by filtration, washed with methanol (5 ml x 2) and dried in vacuo to provide the title compound (189 mg, 82%) as an orange solid. 1H NMR (300 mHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.87 (s, 1H), 8.34-8.36 (d, 2H), 7.71-7, 77 (m, 2H), 7.56-7.59 (d, 1H), 6.82-6.95 (m, 2H), 6.58-6.61 (t, 1H), 4.56- 4.60 (d, 2H), 4.04-4.10 (m, 1H), 3.06-3.13 (m, 2H), 2.40-2.42 (ds, 6H), 1, 86-1.91 (d, 2H), 1.40-1.52 (m, 2H). LC / MS: 459.4 [M-H] +.

Ejemplo 14: Preparacion de (3,4,5,6-tetrahidro-2H-[1,3']bipiridinil-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-iMdenmetM]-2,4-dimetiMH-pirrol-3-carboxiMcoExample 14: Preparation of (3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro -indole- (3Z) -iMdenmetM] -2,4-dimetiMH-pyrrole-3-carboxyMco

imagen20image20

Preparacion de amina BocNHPreparation of BocNH amine

O * *-QO * * -Q

6a6th

BocNHBocNH

-oo-oo

14a14 to

imagen21image21

14b14b

Etapa 1: Se anadieron Pd(dba)3 (0,046 g, 0,05 mmol), Xantphos (0,087 g, 0,15 mmol) y Cs2CO3 (1,1 g, 3,37 mmol) a 20 ml de 1,4-dioxano en una atmosfera de N2, y a esta mezcla se le anadieron el compuesto 6a (0,5 g, 2,5 mmol) y 3-bromopiridina (0,513 g, 3,2 mmol). La mezcla resultante se calento a 100 °C durante 24 h, se enfrio a temperatura ambiente que se recogio en AE (50 ml), y se lavo con salmuera y agua. La fase organica se seco con MgSO4 anhidro y se concentro a presion reducida para dar un residuo que se purifico por cromatografia en columna (PE:AE = 1:2) para proporcionar el compuesto 14a (0,51 g, 73,6 %).Step 1: Pd (dba) 3 (0.046 g, 0.05 mmol), Xantphos (0.087 g, 0.15 mmol) and Cs2CO3 (1.1 g, 3.37 mmol) were added to 20 ml of 1.4 -dioxane in an N2 atmosphere, compound 6a (0.5 g, 2.5 mmol) and 3-bromopyridine (0.513 g, 3.2 mmol) were added to this mixture. The resulting mixture was heated at 100 ° C for 24 h, cooled to room temperature that was collected in EA (50 ml), and washed with brine and water. The organic phase was dried with anhydrous MgSO4 and concentrated under reduced pressure to give a residue which was purified by column chromatography (PE: EA = 1: 2) to provide compound 14a (0.51 g, 73.6%) .

Etapa 2: El compuesto 14a (0,51 g, 1,84 mmol) se disolvio en 10 ml de DCM y se anadieron 3 ml de TFA. La mezcla se agito a temperatura ambiente durante 2 h y se evaporo a sequedad a presion reducida para dar el compuesto en bruto 14b (0,74 g, 99 %).Step 2: Compound 14a (0.51 g, 1.84 mmol) was dissolved in 10 ml of DCM and 3 ml of TFA was added. The mixture was stirred at room temperature for 2 h and evaporated to dryness under reduced pressure to give the crude compound 14b (0.74 g, 99%).

A la solucion de 5-((5-fluoro-2-oxoindolin-3-ilideno) metil)-2,4-dimetil-1H-pirrol-3-carboxilato de (Z)-3H-To the solution of 5 - ((5-fluoro-2-oxoindolin-3-ylidene) methyl) -2,4-dimethyl-1H-pyrrole-3-carboxylate of (Z) -3H-

[1,2,3]triazolo[4,5-b]piridin-3-ilo (A4) (0,1 g, 0,24 mmol) y DIEA (0,074 g, 2,4 equiv.) en 10 ml de una solucion de DMF se le anadio en bruto 14b (0,12 g, 0,29 mmol). La mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml) con sonicacion. El solido se recogio por filtracion, se lavo dos veces con metanol (5 ml) y se seco al vado para proporcionar el compuesto del tftulo (90 mg, rendimiento del 82 %) en forma de un solido de color naranja. rMn 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,89(s, 1H), 8,32-8,33(d, 1H), 7,95-7,97(dd, 1H), 7,74-7,78(dd, 1H), 7,62-7,64(d, 1H), 7,32-7,36(m, 1H), 7,18- 7,22(m,1H), 6,82-6,96(m, 2H), 3,95-3,97(m, 1H), 3,74-3,78(m, 2H), 2,86-2,90(t, 2H), 2,40-2,42(ds, 6H), 1,89-1,93(d, 2H), 1,59-1,68(m, 2H). CL/EM: 460,1 [M+H]+.[1,2,3] triazolo [4,5-b] pyridin-3-yl (A4) (0.1 g, 0.24 mmol) and DIEA (0.074 g, 2.4 equiv.) In 10 ml of a solution of DMF was added crude 14b (0.12 g, 0.29 mmol). The reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml) with sonication. The solid was collected by filtration, washed twice with methanol (5 ml) and dried in vacuo to provide the title compound (90 mg, 82% yield) as an orange solid. rMn 1H (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.89 (s, 1H), 8.32-8.33 (d, 1H), 7.95-7, 97 (dd, 1H), 7.74-7.78 (dd, 1H), 7.62-7.64 (d, 1H), 7.32-7.36 (m, 1H), 7.18- 7.22 (m, 1H), 6.82-6.96 (m, 2H), 3.95-3.97 (m, 1H), 3.74-3.78 (m, 2H), 2, 86-2.90 (t, 2H), 2.40-2.42 (ds, 6H), 1.89-1.93 (d, 2H), 1.59-1.68 (m, 2H). LC / MS: 460.1 [M + H] +.

Ejemplo 15: Preparacion de (4-acetilamino-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol- (3Z)-iMdenmetM]-2,4-dimetiMH-pirrol-3-carboxflicoExample 15: Preparation of (4-acetylamino-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -iMdenmetM] -2,4-dimetiMH-pyrrole- 3-carboxylic

imagen22image22

A la solucion del Ejemplo 4 (1,0 equiv.) y DIEA (2,0 equiv.) en una solucion de DMF se le anadio el compuesto cloruro de acetilo (1,2 equiv.), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol con sonicacion. El solido se recogio por filtracion, se lavo dos veces con metanol y se seco a alto vado para proporcionar el compuesto del tftulo (10 mg, rendimiento del 27 %) enTo the solution of Example 4 (1.0 equiv.) And DIEA (2.0 equiv.) In a DMF solution, the compound acetyl chloride (1.2 equiv.) Was added, and the reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol with sonication. The solid was collected by filtration, washed twice with methanol and dried at high vacuum to provide the title compound (10 mg, 27% yield) in

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forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,90(s, 1H), 7,71-7,78(m, 2H), 7,54-7,60(m, 1H), 6,84-6,95(m, 2H),3,67-3,71(m, 1H), 3,45-3,51(m, 2H),3,31 (s, 3H), 2,38-2,40(ds, 6H), 1,84- 2,00(m,4H), 1,29-1,44(t, 6H). CL/EM: 437,4 [M-H]+.Shape of an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.90 (s, 1H), 7.71-7.78 (m, 2H), 7.54-7, 60 (m, 1H), 6.84-6.95 (m, 2H), 3.67-3.71 (m, 1H), 3.45-3.51 (m, 2H), 3.31 ( s, 3H), 2.38-2.40 (ds, 6H), 1.84-2.00 (m, 4H), 1.29-1.44 (t, 6H). LC / MS: 437.4 [M-H] +.

Ejemplo 16: Preparacion de (4-metanosulfonilamino-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil=1H-pirrol-3-carboxilicoExample 16: Preparation of (4-methanesulfonylamino-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl = 1H- pyrrole-3-carboxylic

imagen23image23

Siguiendo el procedimiento del Ejemplo 15, se obtuvo el compuesto del titulo (21 mg, rendimiento del 84 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,87(s, 1H), 7,71-7,77(m, 2H), 7,52-7,56(m, 1H), 6,82-7,02(m, 3H), 3,63-3,66(m, 1H), 3,07-3,12(m,1H), 2,92(s, 3H), 2,36-2,38(ds, 6H), 1,87-2,01(m,4H), 1,24-1,44(m, 4H). CL/EM: 473,3 [M-H]+.Following the procedure of Example 15, the title compound (21 mg, 84% yield) was obtained. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.87 (s, 1H), 7.71-7.77 (m, 2H), 7.52-7, 56 (m, 1H), 6.82-7.02 (m, 3H), 3.63-3.66 (m, 1H), 3.07-3.12 (m, 1H), 2.92 ( s, 3H), 2.36-2.38 (ds, 6H), 1.87-2.01 (m, 4H), 1.24-1.44 (m, 4H). LC / MS: 473.3 [M-H] +.

Ejemplo 17: Preparacion de (4-hidroxi-1,1-dioxo-tetrahidro-tiofen-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-mdol-(3Z)-iMdenmetM]-2,4-dimetiMH-pirrol-3-carboxiMcoExample 17: Preparation of (4-hydroxy-1,1-dioxo-tetrahydro-thiophene-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -iMdenmetM] -2,4-dimetiMH-pyrrole-3-carboxyMco

imagen24image24

Preparacion de 4-Amino-1,1-dioxo-tetrahidro-tiofen-3-olPreparation of 4-Amino-1,1-dioxo-tetrahydro-thiophene-3-ol

imagen25image25

h2nh2n

10a 17a 17b10a 17a 17b

Etapa 1: A una solucion enfriada del compuesto 10a (2 g, 16,9 mmol) en 11 ml de acido formico al 88 % se le anadio gota a gota peroxido de hidrogeno al 30 % (3 ml). Despues de la adicion, la mezcla se agito durante dos dias a t.a. Se anadio exceso de sulfato de hierro (II) heptahidrato (10 g) para consumir el peroxido de hidrogeno restante. Despues, la mezcla se evaporo a presion reducida para retirar la mayor parte del disolvente. El solido resultante se recogio por filtration, se aclaro con agua y se seco a presion reducida para proporcionar el compuesto 17a (0,6 g, 26 %) en forma de agujas.Step 1: To a cooled solution of compound 10a (2 g, 16.9 mmol) in 11 ml of 88% formic acid, 30% hydrogen peroxide (3 ml) was added dropwise. After the addition, the mixture was stirred for two days at t.a. Excess iron (II) sulfate heptahydrate (10 g) was added to consume the remaining hydrogen peroxide. Then, the mixture was evaporated under reduced pressure to remove most of the solvent. The resulting solid was collected by filtration, rinsed with water and dried under reduced pressure to provide compound 17a (0.6 g, 26%) as needles.

Etapa 2: Se anadio el compuesto 17a (0,60 g, 4,48 mmol) a hidroxido de amoniaco acuoso al 26 % (15 ml) y la mezcla resultante se dejo en agitation durante una noche a t.a. Una pequena cantidad de solido se retiro por filtracion y el filtrado se evaporo a sequedad. El residuo se trituro con eter, acetona y acetato de etilo, y se seco para proporcionar el compuesto 17b en forma de un solido de color blanco (205 mg, 30 %).Step 2: Compound 17a (0.60 g, 4.48 mmol) was added to 26% aqueous ammonia hydroxide (15 ml) and the resulting mixture was allowed to stir overnight at t.a. A small amount of solid was removed by filtration and the filtrate was evaporated to dryness. The residue was triturated with ether, acetone and ethyl acetate, and dried to provide compound 17b as a white solid (205 mg, 30%).

Etapa 3: A la solucion de A4 (150 mg, 0,36 mmol) en 20 ml de DMF se le anadieron el compuesto 17b (110 mg, 0,73 mmol) y DIEA (96 mg, 0,73 mmol), y la mezcla de reaction se agito a t.a. durante varias horas. El analisis por CL/EM se aplico para determinar la finalization de la reaccion. La mezcla de reaccion se evaporo a presion reducida y el residuo se trituro con dietilamina al 5 %/metanol (25 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol y se seco al vacio para proporcionar el compuesto del titulo (110 mg, 71 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,74(s, 1H), 10,92(s, 1H), 7,76-7,79(m, 2H), 7,57-7,59(d, 1H), 6,82-6,97(m, 2H), 5,99-6,00(d, 1H), 4,67-4,72(m, 1H), 4,55(s, 1H),3,42-3,52(m, 2H), 3,25-3,33(m, 2H), 2,45-2,48(ds, 6H). CL/EM: 432,0 [M-H]+.Step 3: To the solution of A4 (150 mg, 0.36 mmol) in 20 ml of DMF, compound 17b (110 mg, 0.73 mmol) and DIEA (96 mg, 0.73 mmol) were added, and The reaction mixture was stirred at rt. for several hours The LC / MS analysis was applied to determine the completion of the reaction. The reaction mixture was evaporated under reduced pressure and the residue was triturated with 5% diethylamine / methanol (25 ml) with sonication. The solid was collected by filtration, washed with methanol and dried in vacuo to provide the title compound (110 mg, 71%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.74 (s, 1H), 10.92 (s, 1H), 7.76-7.79 (m, 2H), 7.57-7, 59 (d, 1H), 6.82-6.97 (m, 2H), 5.99-6.00 (d, 1H), 4.67-4.72 (m, 1H), 4.55 ( s, 1H), 3.42-3.52 (m, 2H), 3.25-3.33 (m, 2H), 2.45-2.48 (ds, 6H). LC / MS: 432.0 [M-H] +.

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Ejemplo 18: Preparacion de (1,1-dioxo-hexahidro-tiopiran-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 18: Preparation of (1,1-dioxo-hexahydro-thiopiran-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxMico

imagen26image26

Preparacion de 1,1-Dioxo-hexahidro-tiopiran-4-ilaminaPreparation of 1,1-Dioxo-hexahydro-thiopiran-4-ylamine

°0 — Qn=Cs — — -^-O? — n-C4° 0 - Qn = Cs - - - ^ - O? - n-C4

o oo o

18a 18b 18c 18d 18e 18f18a 18b 18c 18d 18e 18f

Etapa 1: A una solucion de 18a (2,96 g, 25,5 mmol) en 23 ml de etanol se le anadio NH2OH.HCI (3,64 g, 51 mmol). La mezcla se enfrio a 0 °C en un bano de hielo y se anadio una solucion de NaOH (2,08 g) en 8 ml de H2O. Con la adicion de una solucion de NaOH, se formo un precipitado. La mezcla de reaccion se calento a t.a., se agito durante 2 h mas y se evaporo para retirar el etanol. La solucion acuosa se extrajo con eter. La capa de eter se lavo con agua y salmuera y se seco sobre Na2SO4 anhidro. La capa organica se evaporo a sequedad y el residuo se recristalizo en hexano/eter para dar el compuesto 18b (1,81 g, 54 %).Step 1: To a solution of 18a (2.96 g, 25.5 mmol) in 23 ml of ethanol was added NH2OH.HCI (3.64 g, 51 mmol). The mixture was cooled to 0 ° C in an ice bath and a solution of NaOH (2.08 g) in 8 ml of H2O was added. With the addition of a NaOH solution, a precipitate formed. The reaction mixture was heated to t.a., stirred for a further 2 h and evaporated to remove ethanol. The aqueous solution was extracted with ether. The ether layer was washed with water and brine and dried over anhydrous Na2SO4. The organic layer was evaporated to dryness and the residue was recrystallized from hexane / ether to give compound 18b (1.81 g, 54%).

Etapa 2: A una mezcla de LAH (2,84 g, 75 mmol) en 215 ml de THF se le anadio una solucion del compuesto 18b (1,81 g, 13,8 mmol) en 15 ml de THF con agitacion en refrigeracion con hielo. La mezcla resultante se calento a reflujo durante una noche. Despues de un periodo de refrigeracion, a la mezcla de reaccion se le anadieron 9 ml de NaOH ac. 2 N. El precipitado se retiro por filtracion y se aclaro con THF varias veces. El filtrado se concentro hasta la mitad del volumen y se anadio gota a gota (Boc)2O (3,8 g, 17,4 mmol) con agitacion en refrigeracion con hielo. La mezcla se agito a t.a. durante 2 h, se concentro, se diluyo con acetato de etilo y se lavo con agua. La capa organica se seco sobre MgSO4 anhidro y se evaporo a sequedad. El residuo solido se recristalizo en hexano/eter para dar el compuesto 18d en forma de un solido de color blanco (2,45 g, 81 %).Step 2: A solution of compound 18b (1.81 g, 13.8 mmol) in 15 ml of THF was added to a mixture of LAH (2.84 g, 75 mmol) in 215 ml of THF with stirring in cooling with ice. The resulting mixture was heated at reflux overnight. After a period of refrigeration, 9 ml of aq. NaOH was added to the reaction mixture. 2 N. The precipitate was filtered off and rinsed with THF several times. The filtrate was concentrated to half the volume and added dropwise (Boc) 2O (3.8 g, 17.4 mmol) with stirring under ice cooling. The mixture was stirred at t.a. for 2 h, it was concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The solid residue was recrystallized from hexane / ether to give compound 18d as a white solid (2.45 g, 81%).

Etapa 3: A una solucion del compuesto 18d (509 mg, 2,34 mmol) en 5 ml de THF se le anadio mCPBA al 85 % (1,25 g, 6,15 mmol) con agitacion en refrigeracion con hielo. La mezcla resultante se diluyo con acetato de etilo y se lavo sucesivamente con NaHCO3 ac. saturado, agua y salmuera. La capa organica se seco sobre MgSO4 anhidro y se evaporo a sequedad. El residuo se recristalizo en AE/hexano para dar el compuesto 18e en forma de un solido de color blanco (0,551 g, 94 %). A una solucion de 18e en DCM (15 ml) se le anadio TFA (2,5 ml). La mezcla se agito durante 0,5 h a t.a. y se evaporo para dar el compuesto en bruto 18f (1,12 g) en forma de un aceite de color amarillo que se uso en la siguiente etapa sin purificacion adicional.Step 3: To a solution of compound 18d (509 mg, 2.34 mmol) in 5 ml of THF was added 85% mCPBA (1.25 g, 6.15 mmol) with stirring under ice cooling. The resulting mixture was diluted with ethyl acetate and washed successively with aq NaHCO3. saturated, water and brine. The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was recrystallized from EA / hexane to give compound 18e as a white solid (0.551g, 94%). To a solution of 18e in DCM (15 ml) was added TFA (2.5 ml). The mixture was stirred for 0.5 h at t.a. and evaporated to give crude compound 18f (1.12 g) as a yellow oil that was used in the next step without further purification.

Etapa 4: A la solucion de A4 (107 mg, 0,256 mmol) en 10 ml de una solucion de DMF se le anadieron el compuesto 18f (238 mg) y DIEA (133 mg, 1,03 mmol), y la mezcla de reaccion se agito a t.a. durante varias horas. El analisis por CL/EM se aplico para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (25 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol y se seco al vacio para proporcionar el compuesto del titulo (102 mg, 92 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,89(s, 1H), 7,72-7,78(m, 3H), 6,82-6,96(m, 2H), 4,13-4,15(m, 1H), 3,08-3,12(d, 2H), 2,40-2,42(ds, 6H),1,97-2,16(m, 4H). CL/EM: 430,3 [M-H]+.Step 4: The compound 18f (238 mg) and DIEA (133 mg, 1.03 mmol), and the reaction mixture were added to the solution of A4 (107 mg, 0.256 mmol) in 10 ml of a DMF solution. he stirred at ta for several hours The LC / MS analysis was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (25 ml) with sonication. The solid was collected by filtration, washed with methanol and dried in vacuo to provide the title compound (102 mg, 92%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.89 (s, 1H), 7.72-7.78 (m, 3H), 6.82-6, 96 (m, 2H), 4.13-4.15 (m, 1H), 3.08-3.12 (d, 2H), 2.40-2.42 (ds, 6H), 1.97- 2.16 (m, 4H). LC / MS: 430.3 [M-H] +.

Ejemplo 19: Preparacion de ((1S,2S)-2-hidroxi-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol- (3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 19: Preparation of ((1S, 2S) -2-hydroxy-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2, 4-dimethyl-1H-pyrrole-3-carboxyNico

imagen27image27

A la solucion de A4 (100 mg, 0,24 mmol) y DIEA (140 mg, 0,96 mmol) en 10 ml de DMF se le anadio (1S,2S)-2- Amino-ciclohexanol (45 mg, 0,29 mmol). La mezcla de reaccion se agito a temperatura ambiente durante varias horas. El analisis por CL/EM se aplico para determinar la finalizacion de la reaccion. Se evaporo la DMF a presionTo the solution of A4 (100 mg, 0.24 mmol) and DIEA (140 mg, 0.96 mmol) in 10 ml of DMF was added (1S, 2S) -2- Amino-cyclohexanol (45 mg, 0, 29 mmol). The reaction mixture was stirred at room temperature for several hours. The LC / MS analysis was applied to determine the completion of the reaction. The DMF was evaporated under pressure

reducida y el residuo se precipito con dietilamina al 5 %/metanol (25 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol y se seco al vacio para proporcionar para proporcionar el compuesto del tftulo (70 mg, rendimiento del 74 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMsO-d6): 5 = 13,62(s, 1H), 10,88(s, 1H), 7,71-7,77(m, 2H), 7,36-7,39(d, 1H), 6,81-6,95(m, 2H), 4,58-4,60(d, 1H), 3,48-3,60(m, 1H),3,30-3,35(m, 5 1H), 2,41-2,44(ds, 6H), 1,88-1,90(t, 2H), 1,62(S, 2h), 1,23(s, 4H). CL/EM: 398,1 [M+H]+.reduced and the residue was precipitated with 5% diethylamine / methanol (25 ml) with sonication. The solid was collected by filtration, washed with methanol and dried in vacuo to provide to provide the title compound (70 mg, 74% yield) as an orange solid. 1H NMR (300 MHz, DMsO-d6): 5 = 13.62 (s, 1H), 10.88 (s, 1H), 7.71-7.77 (m, 2H), 7.36-7, 39 (d, 1H), 6.81-6.95 (m, 2H), 4.58-4.60 (d, 1H), 3.48-3.60 (m, 1H), 3.30- 3.35 (m, 5 1H), 2.41-2.44 (ds, 6H), 1.88-1.90 (t, 2H), 1.62 (S, 2h), 1.23 (s , 4H). LC / MS: 398.1 [M + H] +.

Ejemplo 20: Preparacion de ((S)-6-oxo- piperidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 20: Preparation of ((S) -6-oxo-piperidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxNico

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La smtesis del compuesto del tftulo es similar a la del Ejemplo 19 (rendimiento del 19,1 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,71(s, 1H), 10,92(s, 1H), 7,95-7,98(d, 1H),7,72-7,79(m, 2H),6,82-6,96(m, 2H), 4,92-4,96(c, 1H), 4,53-4,89(t, 1H), 3,96-4,02(c, 1H), 2,39-2,43(ds, 6H),1,88-1,90(t, 2H), 1,62(S, 2h), 1,23(s, 4H). CL/EM: 383,2 [M-H]+. 15The synthesis of the title compound is similar to that of Example 19 (19.1% yield): 1H NMR (300 MHz, DMSO-d6): 5 = 13.71 (s, 1H), 10.92 (s, 1H), 7.95-7.98 (d, 1H), 7.72-7.79 (m, 2H), 6.82-6.96 (m, 2H), 4.92-4.96 ( c, 1H), 4.53-4.89 (t, 1H), 3.96-4.02 (c, 1H), 2.39-2.43 (ds, 6H), 1.88-1, 90 (t, 2H), 1.62 (S, 2h), 1.23 (s, 4H). LC / MS: 383.2 [M-H] +. fifteen

Ejemplo 21: Preparacion de ((2S,3S,4R,5S,6S)-3,4,5-trihidroxi-6-hidroximetil-tetrahidro-piran-2-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetM]-2,4-dimetiMH-pirrol-3-carboxflicoExample 21: Preparation of ((2S, 3S, 4R, 5S, 6S) -3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -amide of the acid 5- [5-fluoro-2 -oxo-1,2-dihydro-mdol- (3Z) -ilidenmetM] -2,4-dimetiMH-pyrrole-3-carboxylic

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La sintesis del compuesto del t^tulo es similar a la del Ejemplo 19 (rendimiento del 36,7 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H),10,88(s,1H), 7,95-7,97(d, 1H), 7,71-7,78(m, 2H), 6,82-6,96(m, 2H), 4,84-4,90(t, 1H), 4,70-4,75(m, 2H), 4,56-4,57(m, 1H), 4,38-4,39(d, 1H), 3,71-3,73(t, 1H), 3,29-3,55(m, 5H), 2,44-2,47(ds, 6H). CL/EM:The synthesis of the title compound is similar to that of Example 19 (yield 36.7%): 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.88 ( s, 1H), 7.95-7.97 (d, 1H), 7.71-7.78 (m, 2H), 6.82-6.96 (m, 2H), 4.84-4, 90 (t, 1H), 4.70-4.75 (m, 2H), 4.56-4.57 (m, 1H), 4.38-4.39 (d, 1H), 3.71- 3.73 (t, 1H), 3.29-3.55 (m, 5H), 2.44-2.47 (ds, 6H). LC / MS:

462,1 [M+H]+.462.1 [M + H] +.

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Ejemplo 22: Preparacion de [1-(2-hidroxi-acetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- mdol-(3Z)-ilidenmetN]-2,4-dimetiMH-pirrol-3-carboxflicoExample 22: Preparation of [1- (2-hydroxy-acetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmetN ] -2,4-dimetiMH-pyrrole-3-carboxylic

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imagen31image31

35 Etapa 1: El compuesto 6a (2,12 g, 10,6 mmol) y el compuesto 22a (1,0 g) se pusieron en un reactor para microondas. La mezcla resultante se hizo reaccionar a 160 °C durante 30 min. La mezcla se evaporo y se purifico por cromatografia en columna (AE:PE = 1:1) para proporcionar el compuesto 22b (1,3 g).Step 1: Compound 6a (2.12 g, 10.6 mmol) and compound 22a (1.0 g) were placed in a microwave reactor. The resulting mixture was reacted at 160 ° C for 30 min. The mixture was evaporated and purified by column chromatography (EA: PE = 1: 1) to provide compound 22b (1.3 g).

Etapa 2: A una solucion del compuesto 22b (1,3 g, 5 mmol) en DCM (20 ml) se le anadio TFA (6 ml). La mezcla 40 resultante se agito a t.a. durante aproximadamente 1 h y se evaporo, que se uso para la siguiente etapa sin purificacion adicional.Step 2: To a solution of compound 22b (1.3 g, 5 mmol) in DCM (20 ml) was added TFA (6 ml). The resulting mixture 40 was stirred at t.a. for about 1 h and evaporated, which was used for the next stage without further purification.

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45Four. Five

Etapa 3: A la solucion de A4 (200 mg, 0,478 mmol) y DIEA (0,2 ml, 1,15 mmol) en 25 ml de DMF se le anadio el compuesto 22c (91 mg, 0,57 mmol). La mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol y se seco al vado para proporcionar el compuesto del titulo (180 mg, 86,9 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,88(s, 1H), 7,62-7,78(m, 3H),6,82-6,96(m, 2H), 4,48-4,52(t, 1H), 4,22-4,23(d, 1H), 3,97-4,10(m, 3H), 3,65-3,69(d, 1H), 3,03-3,12(t, 1H), 2,49-2,51 (t, 1H), 2,37-2,40(ds, 6H), 1,80-1,83 (t, 2h), 1,36- 1,46(m, 2H). CL/EM: 439,3 [M-H]+.Step 3: The compound 22c (91 mg, 0.57 mmol) was added to the solution of A4 (200 mg, 0.478 mmol) and DIEA (0.2 ml, 1.15 mmol) in 25 ml of DMF. The reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml) with sonication. The solid was collected by filtration, washed with methanol and dried in vacuo to provide the title compound (180 mg, 86.9%). 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.88 (s, 1H), 7.62-7.78 (m, 3H), 6.82-6, 96 (m, 2H), 4.48-4.52 (t, 1H), 4.22-4.23 (d, 1H), 3.97-4.10 (m, 3H), 3.65- 3.69 (d, 1H), 3.03-3.12 (t, 1H), 2.49-2.51 (t, 1H), 2.37-2.40 (ds, 6H), 1, 80-1.83 (t, 2h), 1.36-1.46 (m, 2H). LC / MS: 439.3 [M-H] +.

Ejemplo 23: Preparacion de [(S)-1-(2-hidroxi-acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 23: Preparation of [(S) -1- (2-hydroxy-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- ( 3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic

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Preparacion de 1-((S)-3-Amino-pirrolidin-1-il)-2-hidroxi-etanonaPreparation of 1 - ((S) -3-Amino-pyrrolidin-1-yl) -2-hydroxy-ethanone

imagen33image33

Siguiendo la preparacion del Compuesto 22c se preparo el compuesto 23c. El compuesto del titulo se preparo siguiendo el Ejemplo 22 (rendimiento del 85,4 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,86(s, 1H), 7,70-7,89(m, 3H), 6,80-6,94(m, 2H), 4,37-4,54(m, 2H), 3,95-4,00(t, 2H), 3,57-3,63(m, 1H), 3,35-3,50(m, 1H), 2,13- 2,14(ds, 6H), 1,86-1,93(m, 4H). CL/EM: 425,4 [M-H]+.Following the preparation of Compound 22c, compound 23c was prepared. The title compound was prepared following Example 22 (85.4% yield): 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.86 (s, 1H), 7.70-7.89 (m, 3H), 6.80-6.94 (m, 2H), 4.37-4.54 (m, 2H), 3.95-4.00 (t, 2H ), 3.57-3.63 (m, 1H), 3.35-3.50 (m, 1H), 2.13-2.14 (ds, 6H), 1.86-1.93 (m , 4H). LC / MS: 425.4 [M-H] +.

Ejemplo 24: Preparacion de (4-hidroxi-tetrahidro-furan-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 24: Preparation of (4-hydroxy-tetrahydro-furan-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2, 4-dimethyl-1H-pyrrole-3-carboxylic

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Preparacion de 4-Amino-tetrahidro-furan-3-olPreparation of 4-Amino-tetrahydro-furan-3-ol

C° — — °'05C ° - - ° '05

^ N^ N

24a 24b 24c24a 24b 24c

Etapa 1: A la solucion de 24a (5,04 g, 0,072 mol) en 150 ml de DCM se le anadio mCPBA al 85 % (18,86 g, 0,093 mol) a 0 °C usando un bano de hielo-agua. La mezcla se agito durante el fin de semana a t.a. y el precipitado se retiro por filtracion. El filtrado se lavo con exito con NaHCO3 acuoso saturado, agua y salmuera. La capa organica se seco sobre Na2SO4 anhidro y se concentro para dar una mezcla de un solido de color blanco y aceite de color amarillo (5,24 g, 84,6 %).Step 1: To the solution of 24a (5.04 g, 0.072 mol) in 150 ml of DCM, 85% mCPBA (18.86 g, 0.093 mol) was added at 0 ° C using an ice-water bath. The mixture was stirred over the weekend at t.a. and the precipitate was removed by filtration. The filtrate was washed successfully with saturated aqueous NaHCO3, water and brine. The organic layer was dried over anhydrous Na2SO4 and concentrated to give a mixture of a white solid and yellow oil (5.24 g, 84.6%).

Etapa 2: Una mezcla del producto en bruto 24b (300 mg, 3,49 mmol) obtenida de la ultima etapa, i-PrOH (3 ml) y NH4OH al 26 % (10 ml) se calento en un tubo cerrado hermeticamente a 80 °C durante 18 h. Una pequena cantidad de solido se retiro por filtracion y el filtrado se evaporo para dar el producto en bruto 24c (0,348 g, 96,8 %).Stage 2: A mixture of the crude product 24b (300 mg, 3.49 mmol) obtained from the last stage, i-PrOH (3 ml) and 26% NH4OH (10 ml) was heated in a tightly sealed tube at 80 ° C for 18 h. A small amount of solid was removed by filtration and the filtrate was evaporated to give the crude product 24c (0.348 g, 96.8%).

Etapa 3: A la solucion de A4 (199 mg, 0,476 mmol) en 20 ml de DMF se le anadio el compuesto 24c (0,348 g, 3,378 mmol), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml). Despues, la suspension se puso en un refrigerador durante una noche y seStep 3: To the solution of A4 (199 mg, 0.476 mmol) in 20 ml of DMF, compound 24c (0.348 g, 3.378 mmol) was added, and the reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml). Then, the suspension was put in a refrigerator overnight and it

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concentro para retirar la mayor parte de los disolventes. A la suspension de color amarillo resultante se le anadio etanol y se concentro para retirar la mayor parte del disolvente. Despues, la suspension de color amarillo resultante se puso en un refrigerador durante una hora y el precipitado se recogio por filtracion, se lavo con etanol y se seco al vado para dar el compuesto del trtulo en forma de un solido de color naranja (170 mg, rendimiento del 93 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H),10,88(s, 1H), 7,71-7,78(m, 3H),6,82-6,96(m, 2H), 5,25-5,27(d, 1H), 4,14- 4,19(m, 2H), 3,96-4,00(c, 1H),3,86-3,90(c, 1H), 3,52-3,63(m, 2H), 2,39-2,41 (ds,6H). CL/EM: 384,3 [M+H]+.Concentrate to remove most of the solvents. To the resulting yellow suspension was added ethanol and concentrated to remove most of the solvent. Then, the resulting yellow suspension was placed in a refrigerator for one hour and the precipitate was collected by filtration, washed with ethanol and dried in the vacuum to give the title compound as an orange solid (170 mg , 93% yield). 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.88 (s, 1H), 7.71-7.78 (m, 3H), 6.82-6, 96 (m, 2H), 5.25-5.27 (d, 1H), 4.14-4.19 (m, 2H), 3.96-4.00 (c, 1H), 3.86- 3.90 (c, 1H), 3.52-3.63 (m, 2H), 2.39-2.41 (ds, 6H). LC / MS: 384.3 [M + H] +.

Ejemplo 25: Preparacion de ((S)-2-oxo- pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 25: Preparation of ((S) -2-oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxylic

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Preparacion de (S)-3-Amino-pirrolidin-2-onaPreparation of (S) -3-Amino-pyrrolidin-2-one

h^N-^Aoh __ CNh ^ N- ^ Aoh __ CN

2HCI NHz N 02HCI NHz N 0

25a 25b25a 25b

Etapa 1: Se anadio gota a gota HMDS (67 ml, 0,32 mol) en ACN (50 ml) a una solucion de 25a (5 g, 32 mmol) en ACN (50 ml) a temperatura ambiente. La mezcla resultante se calento a reflujo durante 48 h bajo la proteccion de N2. Cuando la reaccion se completo, la mezcla se enfrio, se vertio en metanol frio (50 ml) y se agito durante 30 min. La mezcla obtenida se evaporo a sequedad y el residuo se extrajo con cloroformo (150 ml x 3) a reflujo. La solucion de cloroformo combinada se evaporo para proporcionar el producto en bruto 25b (3,1 g, 96 %).Step 1: HMDS (67 ml, 0.32 mol) in ACN (50 ml) was added dropwise to a solution of 25a (5 g, 32 mmol) in ACN (50 ml) at room temperature. The resulting mixture was heated at reflux for 48 h under the protection of N2. When the reaction was complete, the mixture was cooled, poured into cold methanol (50 ml) and stirred for 30 min. The obtained mixture was evaporated to dryness and the residue was extracted with chloroform (150 ml x 3) under reflux. The combined chloroform solution was evaporated to provide the crude product 25b (3.1 g, 96%).

Etapa 2: A la solucion de A4 (334 mg, 0,8 mmol) y DIEA (1 ml) en 20 ml de DMF se le anadio 25b (120 mg, 1,28 mmol). La mezcla de reaccion se agito a temperatura ambiente durante varias horas. El analisis por CL/EM se aplico para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml). El precipitado se recogio por filtracion, se lavo con etanol y se seco al vado para dar el compuesto del titulo en forma de un solido de color naranja (83 mg, rendimiento del 27 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H),10,89(s,1H), 7,71-7,82(m, 4H),6,82-6,96(m, 2H), 4,47-4,56(c, 1H),3,18- 3,25(m, 2H), 2,42-2,45(ds, 6H), 2,27-2,39(m, 1H), 1,92-2,00(c,1H). CL/EM: 383,0 [M+H]+.Step 2: To the solution of A4 (334 mg, 0.8 mmol) and DIEA (1 ml) in 20 ml of DMF was added 25b (120 mg, 1.28 mmol). The reaction mixture was stirred at room temperature for several hours. The LC / MS analysis was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml). The precipitate was collected by filtration, washed with ethanol and dried in vacuo to give the title compound as an orange solid (83 mg, 27% yield). 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.89 (s, 1H), 7.71-7.82 (m, 4H), 6.82-6, 96 (m, 2H), 4.47-4.56 (c, 1H), 3.18-3.25 (m, 2H), 2.42-2.45 (ds, 6H), 2.27- 2.39 (m, 1H), 1.92-2.00 (c, 1H). LC / MS: 383.0 [M + H] +.

Ejemplo 26: Preparacion de (1-bencil-4-hidroxi-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 26: Preparation of (1-benzyl-4-hydroxy-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxylic

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Preparacion de 4-Amino-1-bencil-pirrolidin-3-olPreparation of 4-Amino-1-benzyl-pyrrolidin-3-ol

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Etapa 1: A una solucion enfriada con hielo de 26a (4,77 g, 30 mmol), H2SO4 al 98 % (1,95 ml), H2O (4,5 ml) y acetona (30 ml) se le anadio mCPBA al 85 % (7,91 g, 39 mmol) con agitacion. La mezcla se dejo reaccionar durante 48 h a t.a. Se evaporo la acetona y la mezcla se neutralizo con NaOH ac. 1 N y se extrajo con tolueno. La fase organica se seco sobre MgSO4 anhidro y se evaporo. El residuo se purifico por cromatografia en columna (AE:PE = 1:4) para proporcionar 26b (2,0 g, 38 %).Step 1: To an ice-cold solution of 26a (4.77 g, 30 mmol), 98% H2SO4 (1.95 ml), H2O (4.5 ml) and acetone (30 ml) mCPBA was added to the 85% (7.91 g, 39 mmol) with stirring. The mixture was allowed to react for 48 h at t.a. Acetone was evaporated and the mixture was neutralized with aq. NaOH. 1 N and extracted with toluene. The organic phase was dried over anhydrous MgSO4 and evaporated. The residue was purified by column chromatography (EA: PE = 1: 4) to provide 26b (2.0 g, 38%).

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Etapa 2: Una mezcla de 26b (618 mg, 3,53 mmol) en 10 ml de hidroxido de amonio al 26 % se calento en un tubo cerrado hermeticamente a 110 °C durante 24 h. Una pequena cantidad de solido se retiro por filtracion y el filtrado se evaporo para dar el producto en bruto 26c (630 mg, rendimiento del 93 %).Step 2: A mixture of 26b (618 mg, 3.53 mmol) in 10 ml of 26% ammonium hydroxide was heated in a tightly sealed tube at 110 ° C for 24 h. A small amount of solid was removed by filtration and the filtrate was evaporated to give crude product 26c (630 mg, 93% yield).

Etapa 3: A la solucion de A4 (493 mg, 1,18 mmol) en 50 ml de DMF se le anadio el compuesto 26c (0,455 mg, 2,37 mmol), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. El analisis por CL/EM se aplico para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol. El precipitado se recogio por filtracion, se lavo con etanol y se seco al vado para dar el compuesto del tftulo (517 mg, rendimiento del 92,5 %) un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H),10,87(s, 1H), 7,71-7,77(m, 3H),7,22-7,32(m, 5H), 6,82-6,95(m, 2H), 5,03-5,05(d, 1H), 4,06-4,15(m, 2H), 3,50-3,64(c, 2H), 2,82-2,89(m, 2H), 2,35-2,41(m,8H). CL/EM: 475,2 [M+H]+.Step 3: The compound 26c (0.455 mg, 2.37 mmol) was added to the solution of A4 (493 mg, 1.18 mmol) in 50 ml of DMF, and the reaction mixture was stirred at room temperature for several hours. The LC / MS analysis was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol. The precipitate was collected by filtration, washed with ethanol and dried in vacuo to give the title compound (517 mg, 92.5% yield) an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.87 (s, 1H), 7.71-7.77 (m, 3H), 7.22-7, 32 (m, 5H), 6.82-6.95 (m, 2H), 5.03-5.05 (d, 1H), 4.06-4.15 (m, 2H), 3.50- 3.64 (c, 2H), 2.82-2.89 (m, 2H), 2.35-2.41 (m, 8H). LC / MS: 475.2 [M + H] +.

Ejemplo 27: Preparacion de (1-acetil-4-hidroxi-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 27: Preparation of (1-acetyl-4-hydroxy-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxMico

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Una mezcla de Ejemplo 26 (283,7 mg, 0,59 mmol), Pd al 10 %/C (282 mg) y acido acetico (3 gotas) en 30 ml de [DMF:MeOH = 1:1] se agito a t.a. en una atmosfera de H2. Despues de que la reaccion se completase segun se detecto por CL/EM, el catalizador se retiro por filtracion y el filtrado se evaporo a sequedad. El residuo se trituro con etanol para proporcionar (4-hidroxi-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-A mixture of Example 26 (283.7 mg, 0.59 mmol), 10% Pd / C (282 mg) and acetic acid (3 drops) in 30 ml of [DMF: MeOH = 1: 1] was stirred at ta in an atmosphere of H2. After the reaction was completed as detected by LC / MS, the catalyst was filtered off and the filtrate was evaporated to dryness. The residue was triturated with ethanol to provide 5- (5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - (4-hydroxy-pyrrolidin-3-yl) -amide.

2,4-dimetil-1 H-pirrol- 3-carboxHico (178 mg, 67 %).2,4-dimethyl-1 H-pyrrole-3-carboxico (178 mg, 67%).

A la solucion de (4-hidroxi-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxHico (150 mg, 0,39 mmol) y DIEA (89 mg, 0,69 mmol) se le anadio Ch3COCI (33,7 mg, 0,43 mmol) en un bano de hielo. La mezcla se agito a t.a. durante 3 h. Despues de que la reaccion se completas, se evaporo la DMF a presion reducida y el residuo se trituro con metanol, y el solido se recogio por filtracion, se lavo con etanol y se seco al vado para dar el compuesto del tftulo (82 mg, rendimiento del 57 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,87(s, 1H), 8,07-8,10(d, 1H), 7,71-7,85(m, 3H),To the solution of (4-hydroxy-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1H-pyrrole-3-carboxico (150 mg, 0.39 mmol) and DIEA (89 mg, 0.69 mmol) were added Ch3COCI (33.7 mg, 0.43 mmol) in an ice bath. The mixture was stirred at t.a. for 3 h. After the reaction is complete, the DMF is evaporated under reduced pressure and the residue is triturated with methanol, and the solid is collected by filtration, washed with ethanol and dried in vat to give the title compound (82 mg, 57% yield) in the form of an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.87 (s, 1H), 8.07-8.10 (d, 1H), 7.71-7, 85 (m, 3H),

6,82-6,92(m, 2H), 5,34-5,44(dd, 1H), 4,13-4,18(d, 2H), 3,67-3,81(m, 4H), 2,38-2,40(ds, 6H), 1,92-1,93(d,3H). CL/EM: 427,0 [M+H]+.6.82-6.92 (m, 2H), 5.34-5.44 (dd, 1H), 4.13-4.18 (d, 2H), 3.67-3.81 (m, 4H ), 2.38-2.40 (ds, 6H), 1.92-1.93 (d, 3H). LC / MS: 427.0 [M + H] +.

Ejemplo 28: Preparacion de (1-dimetilaminooxalil- piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 28: Preparation of (1-dimethylaminooxalyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4- dimethyl-1H-pyrrole-3-carboxMico

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Preparacion de 2-(4-Amino-piperidin-1-il)-N,N-dimetil-2-oxo-acetamidaPreparation of 2- (4-Amino-piperidin-1-yl) -N, N-dimethyl-2-oxo-acetamide

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Etapa 1: Se anadio DIEA (0,87 ml, 5 mmol) a una solucion enfriada con hielo de cloruro de oxalilo (0,22 ml, 2,5 mmol) y dimetilamina (0,204 g, 2,5 mmol) en 30 ml de THF. La mezcla se agito a t.a. durante 1 h, que se uso en la siguiente etapa directamente.Step 1: DIEA (0.87 ml, 5 mmol) was added to an ice-cold solution of oxalyl chloride (0.22 ml, 2.5 mmol) and dimethylamine (0.204 g, 2.5 mmol) in 30 ml of THF. The mixture was stirred at t.a. for 1 h, which was used in the next stage directly.

Etapa 2: El compuesto 6a (0,5 g, 2,5 mmol) se anadio a la solucion anterior seguido de DIEA (0,87 ml, 5 mmol). La mezcla resultante se agito a t.a. durante una noche y se evaporo. El residuo se purifico por cromatografia en columna para proporcionar 28b (307 mg, 41 %).Step 2: Compound 6a (0.5 g, 2.5 mmol) was added to the above solution followed by DIEA (0.87 ml, 5 mmol). The resulting mixture was stirred at t.a. overnight and evaporated. The residue was purified by column chromatography to provide 28b (307 mg, 41%).

5 Etapa 3: A una solucion del compuesto 28b (172 mg, 0,57 mmol) en 5 ml de DCM se le anadio TFA (0,66 ml, 8,6 mmol). La mezcla resultante se agito a t.a. durante aprox. 1 h y se evaporo. El residuo se anadio a una solucion de A4 (159 mg, 0,38 mmol) y DIEA (1 ml) en 20 ml de DMF. La mezcla de reaccion se agito a temperatura ambiente durante varias horas. El analisis por CL/EM se aplico para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml). El precipitado se recogio por 10 filtracion, se lavo con metanol y se seco al vacio para dar un solido de color naranja (169 mg, rendimiento del 92,5 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,89(s, 1H), 7,64-7,78(m, 3H),6,82-6,96(m, 2H), 4,03- 4,23(m, 2H), 3,38-3,49(m, 1H), 3,16-3,29(m, 1H), 2,87-2,99(m, 7H), 2,39-2,42(ds, 6H), 1,87-1,90(m,2H), 1,40- 1,49(m, 2H). CL/EM: 482,1 [M+H]+.Step 3: To a solution of compound 28b (172 mg, 0.57 mmol) in 5 ml of DCM was added TFA (0.66 ml, 8.6 mmol). The resulting mixture was stirred at t.a. for approx. 1 h and evaporated. The residue was added to a solution of A4 (159 mg, 0.38 mmol) and DIEA (1 ml) in 20 ml of DMF. The reaction mixture was stirred at room temperature for several hours. The LC / MS analysis was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml). The precipitate was collected by filtration, washed with methanol and dried in vacuo to give an orange solid (169 mg, 92.5% yield): 1 H NMR (300 MHz, DMSO-d6): 5 = 13 , 68 (s, 1H), 10.89 (s, 1H), 7.64-7.78 (m, 3H), 6.82-6.96 (m, 2H), 4.03-4.23 (m, 2H), 3.38-3.49 (m, 1H), 3.16-3.29 (m, 1H), 2.87-2.99 (m, 7H), 2.39-2 , 42 (ds, 6H), 1.87-1.90 (m, 2H), 1.40-1.49 (m, 2H). LC / MS: 482.1 [M + H] +.

15 Ejemplo 29: Preparacion de ((S)-l-dimetilaminooxalil- pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 29: Preparation of ((S) -l-dimethylaminooxalyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

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20 La preparacion de 2-((S)-3-Amino-pirrolidin-1-il)-N,N-dimetil-2-oxo-acetamida (29b) es similar a la de 28c:The preparation of 2 - ((S) -3-Amino-pyrrolidin-1-yl) -N, N-dimethyl-2-oxo-acetamide (29b) is similar to that of 28c:

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29a 29b29a 29b

La sintesis del compuesto del titulo es similar a la del Ejemplo 28 (32 mg, rendimiento del 53,9 %). RMN 1H 25 (300 MHz, DMSO-d6): 5 = 13,67-13,68(d, 1H), 10,87(s, 1H), 7,71-7,92(m, 3H),6,82-6,93(m, 2H), 4,40-4,47(m, 1H),The synthesis of the title compound is similar to that of Example 28 (32 mg, 53.9% yield). 1H NMR 25 (300 MHz, DMSO-d6): 5 = 13.67-13.68 (d, 1H), 10.87 (s, 1H), 7.71-7.92 (m, 3H), 6 , 82-6.93 (m, 2H), 4.40-4.47 (m, 1H),

3,39-3,62(m, 4H), 2,86-2,92(dd, 6H), 2,39-2,41 (dd, 6H), 2,15-2,18(m, 1H), 1,94-2,13(m, 1H). CL/EM: 466,4 [M-H]+.3.39-3.62 (m, 4H), 2.86-2.92 (dd, 6H), 2.39-2.41 (dd, 6H), 2.15-2.18 (m, 1H ), 1.94-2.13 (m, 1H). LC / MS: 466.4 [M-H] +.

Ejemplo 30: Preparacion de [4-(morfolina-4-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 30: Preparation of [4- (morpholine-4-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2, 4-dimethyl-1H-pyrrole-3-carboxMico

3030

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Etapa 1: Se anadio acido 4-amino-ciclohexanocarboxilico (84 mg, 0,573 mmol) a una solucion de A4 (200 mg, 0,478 mmol) y DIEA (0,125 ml, 0,717 mmol) en 15 ml de DMF. La mezcla se agito a t.a. Se uso CL-EM para 35 determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se trituro con ACN varias veces para proporcionar acido 4-({5-[5-fluoro-2-oxo-1,2-dihidro-indoI-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3- carbonil}-amino)-ciclohexanocarboxilico (180 mg, 88,5 %).Step 1: 4-Amino-cyclohexanecarboxylic acid (84 mg, 0.573 mmol) was added to a solution of A4 (200 mg, 0.478 mmol) and DIEA (0.125 ml, 0.717 mmol) in 15 ml of DMF. The mixture was stirred at t.a. CL-MS was used to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue triturated with ACN several times to provide acid 4 - ({5- [5-fluoro-2-oxo-1,2-dihydro-indoI- (3Z) -ylidenemethyl] -2) , 4-dimethyl-1H-pyrrole-3-carbonyl} -amino) -cyclohexanecarboxylic acid (180 mg, 88.5%).

Etapa 2: A la solucion de acido 4-({5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3- 40 carbonil}-amino)-ciclohexanocarboxilico en 20 ml de DMF se le anadieron HATU (0,161 g, 0,424 mmol), DIEA (0,072 ml, 0,424 mmol) y morfolina (0,0737 g, 0,847 mmol). La mezcla de reaccion se agito a t.a. durante una noche. Se uso CL-EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (5 ml). El precipitado se recogio por filtracion, se lavo con metanol y se secoStep 2: To the acid solution 4 - ({5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1H-pyrrole-3- Carbonyl} -amino) -cyclohexanecarboxylic in 20 ml of DMF was added HATU (0.161 g, 0.424 mmol), DIEA (0.072 ml, 0.424 mmol) and morpholine (0.0737 g, 0.847 mmol). The reaction mixture was stirred at t.a. during one night CL-EM was used to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (5 ml). The precipitate was collected by filtration, washed with methanol and dried

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al vacio para dar el compuesto del titulo (69 mg, rendimiento del 32,9 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,87(s,1H), 7,71-7,77(m, 2H),7,53-7,55(d, 1H), 6,81-6,92(m, 2H),3,95-3,96(m, 1H), 3,29-3,54(m, 8H),2,64-2,67(m, 1H), 2,39-2,41(ds,6H), 1,47-1,88(m, 8H). CL/EM: 495,1 [M+H]+.in vacuo to give the title compound (69 mg, 32.9% yield) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.87 (s, 1H), 7.71-7.77 (m, 2H), 7.53-7, 55 (d, 1H), 6.81-6.92 (m, 2H), 3.95-3.96 (m, 1H), 3.29-3.54 (m, 8H), 2.64- 2.67 (m, 1H), 2.39-2.41 (ds, 6H), 1.47-1.88 (m, 8H). LC / MS: 495.1 [M + H] +.

Ejemplo 31: Preparacion de [4-(pirrolidina-1-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 31: Preparation of [4- (pyrrolidine-1-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2, 4-dimethyl-1H-pyrrole-3-carboxyNico

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La smtesis del compuesto del titulo es similar a la del Ejemplo 30 (92 mg, rendimiento del 67,8 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,64(s, 1H), 10,86(s, 1H), 7,70-7,76(m, 2H), 7,52-7,55(d, 1H), 6,80-6,94(m, 2H), 3,93- 3,95(m, 1H), 3,41-3,46(m, 2H), 3,22-3,28(m, 3H), 2,40-2,42(ds, 6H), 1,68-1,90(m, 8H), 1,45-1,60(m, 4H). CL/EM:The synthesis of the title compound is similar to that of Example 30 (92 mg, 67.8% yield): 1H NMR (300 MHz, DMSO-d6): 5 = 13.64 (s, 1H), 10.86 (s, 1H), 7.70-7.76 (m, 2H), 7.52-7.55 (d, 1H), 6.80-6.94 (m, 2H), 3.93-3 , 95 (m, 1H), 3.41-3.46 (m, 2H), 3.22-3.28 (m, 3H), 2.40-2.42 (ds, 6H), 1.68 -1.90 (m, 8H), 1.45-1.60 (m, 4H). LC / MS:

479,1 [M+H]+.479.1 [M + H] +.

Ejemplo 32: Preparacion de [4-(aziridina-1-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 32: Preparation of [4- (aziridine-1-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2, 4-dimethyl-1H-pyrrole-3-carboxMico

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La sintesis del compuesto del tUulo es similar a la del Ejemplo 30: CL/EM: 449,3 [M-H]+.The synthesis of the title compound is similar to that of Example 30: LC / MS: 449.3 [M-H] +.

Ejemplo 33: Preparacion de [(1R,3S)-3-(pirrolidina-1-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-Example 33: Preparation of [(1R, 3S) -3- (pyrrolidine-1-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-

1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMico1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

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La smtesis del compuesto del titulo es similar a la del Ejemplo 30: RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,88(s, 1H), 7,71-7,80(m, 3H), 6,81-6,95(m, 2H), 4,29-4,31(m, 1H), 3,38-3,0(m, 2H), 3,17-3,30(m, 2H), 3,01-3,06(m, 1H), 2,42-2,43(ds, 6H), 1,65-2,08(m, 10H). CL/EM: 465,2 [M+H]+.The synthesis of the title compound is similar to that of Example 30: 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.88 (s, 1H), 7.71-7 , 80 (m, 3H), 6.81-6.95 (m, 2H), 4.29-4.31 (m, 1H), 3.38-3.0 (m, 2H), 3.17 -3.30 (m, 2H), 3.01-3.06 (m, 1H), 2.42-2.43 (ds, 6H), 1.65-2.08 (m, 10H). LC / MS: 465.2 [M + H] +.

Ejemplo 34: Preparacion de [(1R,3S)-3-(morfolina-4- carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-Example 34: Preparation of [(1R, 3S) -3- (morpholine-4-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-

1,2-dihidro-mdol-(3Z)-ilidenmetM]-2,4-dimetiMH-pirrol-3-carboxMico1,2-dihydro-mdol- (3Z) -ylidenmetM] -2,4-dimetiMH-pyrrole-3-carboxMico

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La sintesis del compuesto del titulo es similar a la del Ejemplo 30: RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,88(s, 1H), 7,64-7,78(m, 3H), 6,81-6,95(m, 2H), 4,25-4,31(m, 1H), 3,38-3,55(m, 8H), 3,14-3,19(m, 1H), 2,41- 2,42(ds, 6H), 1,62-2,08(m, 10H). CL/EM: 481,2 [M+H]+.The synthesis of the title compound is similar to that of Example 30: 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.88 (s, 1H), 7.64-7 , 78 (m, 3H), 6.81-6.95 (m, 2H), 4.25-4.31 (m, 1H), 3.38-3.55 (m, 8H), 3.14 -3.19 (m, 1H), 2.41-2.42 (ds, 6H), 1.62-2.08 (m, 10H). LC / MS: 481.2 [M + H] +.

Ejemplo 35: Preparacion de [(1R,3S)-3-(aziridina-1-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetiMH-pirrol-3-carboxilicoExample 35: Preparation of [(1R, 3S) -3- (aziridine-1-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ilidenmethyl] -2,4-dimetiMH-pyrrole-3-carboxylic

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La sintesis del compuesto del titulo es similar a la del Ejemplo 30: CL/EM: 435,2 [M-H]+.The synthesis of the title compound is similar to that of Example 30: LC / MS: 435.2 [M-H] +.

Ejemplo 36: Preparacion de [(1R,2S)-2-(pirrolidina-1-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-Example 36: Preparation of [(1R, 2S) -2- (pyrrolidine-1-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-

1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilico1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic acid

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La sintesis del compuesto del titulo es similar a la del Ejemplo 30: RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,88(s, 1H), 7,70-7,77(m, 2H), 7,40-7,42(d, 2H), 6,82-6,93(m, 2H), 4,52-4,61(m, 1H), 3,62-3,70(m, 2H), 3,42- 3,51(m, 1H), 3,09-3,30(m, 3H), 2,38-2,41(ds, 6H), 1,49-1,98(m, 10H). CL/EM: 465,1 [M+H]+.The synthesis of the title compound is similar to that of Example 30: 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.88 (s, 1H), 7.70-7 , 77 (m, 2H), 7.40-7.42 (d, 2H), 6.82-6.93 (m, 2H), 4.52-4.61 (m, 1H), 3.62 -3.70 (m, 2H), 3.42-3.51 (m, 1H), 3.09-3.30 (m, 3H), 2.38-2.41 (ds, 6H), 1 , 49-1.98 (m, 10H). LC / MS: 465.1 [M + H] +.

Ejemplo 37: Preparacion de [(1R,2S)-2-(morfolina-4-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo- 1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 37: Preparation of [(1R, 2S) -2- (morpholine-4-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic

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La smtesis del compuesto del titulo es similar a la del Ejemplo 30: RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,88(s, 1H), 7,70-7,77(m, 2H), 7,30-7,33(d, 1H), 6,81-6,93(m, 2H), 4,56-4,63(m, 1H), 3,37-3,60(m, 8H), 3,21- 3,27(m, 1H), 2,38-2,42(ds, 6H), 1:45-2,06(m, 6H). CL/EM: 481,1 [M+H]+.The synthesis of the title compound is similar to that of Example 30: 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.88 (s, 1H), 7.70-7 , 77 (m, 2H), 7.30-7.33 (d, 1H), 6.81-6.93 (m, 2H), 4.56-4.63 (m, 1H), 3.37 -3.60 (m, 8H), 3.21-27 (m, 1H), 2.38-2.42 (ds, 6H), 1: 45-2.06 (m, 6H). LC / MS: 481.1 [M + H] +.

Ejemplo 38: Preparacion de [(1R,2S)-2- (aziridina-1-carbonil)-ciclopentil]-amida del acido 5-[5-fluoro-2-oxo-Example 38: Preparation of [(1R, 2S) -2- (aziridine-1-carbonyl) -cyclopentyl] -amide of the acid 5- [5-fluoro-2-oxo-

1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilico1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic acid

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La smtesis del compuesto del titulo es similar a la del Ejemplo 30: CL/EM: 435,3 [M-H]+.The synthesis of the title compound is similar to that of Example 30: LC / MS: 435.3 [M-H] +.

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A la solucion de A4 (200 mg, 0,478 mmol) y DIEA (1 ml) en 20 ml de DMF se le anadio el compuesto 39a (225 mg, 0,623 mmol), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml). El precipitado se recogio por filtracion, se lavo con metanol y se seco al vado para dar en bruto 39b que se disolvio en 5 ml de TFA al 95 % a t.a. durante 0,5 h. Despues, la mezcla se evaporo a sequedad y el residuo se trituro con metanol varias veces para proporcionar el compuesto del titulo (89 mg, rendimiento del 43 %). CL/EM: 432,2 [M+H]+.To the solution of A4 (200 mg, 0.478 mmol) and DIEA (1 ml) in 20 ml of DMF compound 39a (225 mg, 0.623 mmol) was added, and the reaction mixture was stirred at room temperature for several hours . CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml). The precipitate was collected by filtration, washed with methanol and dried in vacuo to give crude 39b which was dissolved in 5 ml of 95% TFA at t.a. for 0.5 h. Then, the mixture was evaporated to dryness and the residue was triturated with methanol several times to provide the title compound (89 mg, 43% yield). LC / MS: 432.2 [M + H] +.

Ejemplo 40: Preparacion de ((S)-1-carbamoilmetil-2-oxo-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 40: Preparation of ((S) -1-carbamoylmethyl-2-oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico

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Preparacion de 2-((S)-3-Amino-2-oxo-pirrolidin-1-il)-acetamidaPreparation of 2 - ((S) -3-Amino-2-oxo-pyrrolidin-1-yl) -acetamide

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25b 40a 40b 40c 40d25b 40a 40b 40c 40d

Etapa 1: A una solucion de 25b (3,1 g, 32 mmol) en metanol (130 ml) se le anadieron TEA (16 ml) y (Boc)2O (7,7 g, 35,2 mmol) a temperatura ambiente. La mezcla se agito durante una noche a temperatura ambiente, seguido de calentamiento a reflujo durante 2 h. El disolvente se retiro y el residuo se purifico por cromatografia en columna (AE) para proporcionar 40a (5,0 g, 78 %) en forma de un solido de color blanco.Step 1: To a solution of 25b (3.1 g, 32 mmol) in methanol (130 ml) were added TEA (16 ml) and (Boc) 2O (7.7 g, 35.2 mmol) at room temperature . The mixture was stirred overnight at room temperature, followed by heating under reflux for 2 h. The solvent was removed and the residue was purified by column chromatography (EA) to provide 40a (5.0 g, 78%) as a white solid.

Etapa 2: A una solucion de 40a (700 mg, 3,5 mmol) en THF (50 ml) se le anadio NaH al 60 % (560 mg, 14 mmol) a 0 °C. Despues de agitar durante 1 h a 0 °C, se anadio bromoacetato de etilo (700 mg, 4,2 mmol) y la mezcla se agito a temperatura ambiente durante una noche. Despues de que la reaccion se completase, la mezcla se diluyo con AE (50 ml) y se inactivo con salmuera (50 ml). Las capas organicas y acuosas se separaron. La capa acuosa se extrajo por AE (50 ml x 3). La fase de AE combinada se seco por Na2sO4 anhidro y se evaporo para proporcionar en bruto 40b (1,0 g, 99 %).Step 2: To a solution of 40a (700 mg, 3.5 mmol) in THF (50 ml) was added 60% NaH (560 mg, 14 mmol) at 0 ° C. After stirring for 1 h at 0 ° C, ethyl bromoacetate (700 mg, 4.2 mmol) was added and the mixture was stirred at room temperature overnight. After the reaction was complete, the mixture was diluted with EA (50 ml) and quenched with brine (50 ml). The organic and aqueous layers were separated. The aqueous layer was extracted by EA (50 ml x 3). The combined EA phase was dried over anhydrous Na2sO4 and evaporated to give crude 40b (1.0 g, 99%).

Etapa 3: Se burbujeo gas NH3 durante 1 h en una solucion de 40b (0,27 g, 0,94 mmol) en MeOH (20 ml). La solucion se mantuvo en agitacion a t.a. durante 24 h. El disolvente se evaporo y el residuo se purifico por cromatografia en columna para proporcionar 40c (170 mg, 70,3 %). A una solucion del compuesto 40c (160 mg, 0,62 mmol) en 5 mlStep 3: NH3 gas was bubbled for 1 h in a solution of 40b (0.27 g, 0.94 mmol) in MeOH (20 ml). The solution was kept under stirring at t.a. for 24 h. The solvent was evaporated and the residue was purified by column chromatography to provide 40c (170 mg, 70.3%). To a solution of compound 40c (160 mg, 0.62 mmol) in 5 ml

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de DCM se le anadio TFA (0,66 ml, 8,6 mmol). La mezcla resultante se agito a t.a. durante aproximadamente 1 h y se evaporo. El residuo se anadio a una solucion de A4 (172 mg, 0,41 mmol) y DIEA (0,22 ml, 1,23 mmol) en 20 ml de DMF. La mezcla de reaccion se agito a temperatura ambiente durante varias horas. El analisis por CL/EM se aplico para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml). El precipitado se recogio por filtracion, se lavo con etanol y se seco al vado para dar el compuesto del titulo en forma de un solido de color naranja (136 mg, rendimiento del 75,3 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,71(s, 1H), 10,92(s, 1H), 7,95-8,00(t, 1H), 7,73-7,79(m, 2H), 7,22-7,42(ds, 2H), 6,82- 6,97(m, 2H), 4,53-4,62(c, 1H), 3,73-3,87(c,2H), 3,37-3,46(m, 2H), 2,39-2,40(ds,6H), 1,95-2,02(m, 1H). CL/EM: 440,0 [M+H]+.TFA (0.66 ml, 8.6 mmol) was added to DCM. The resulting mixture was stirred at t.a. for about 1 h and evaporated. The residue was added to a solution of A4 (172 mg, 0.41 mmol) and DIEA (0.22 ml, 1.23 mmol) in 20 ml of DMF. The reaction mixture was stirred at room temperature for several hours. The LC / MS analysis was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml). The precipitate was collected by filtration, washed with ethanol and dried in vacuo to give the title compound as an orange solid (136 mg, 75.3% yield). 1H NMR (300 MHz, DMSO-d6): 5 = 13.71 (s, 1H), 10.92 (s, 1H), 7.95-8.00 (t, 1H), 7.73-7, 79 (m, 2H), 7.22-7.42 (ds, 2H), 6.82-6.97 (m, 2H), 4.53-4.62 (c, 1H), 3.73- 3.87 (c, 2H), 3.37-3.46 (m, 2H), 2.39-2.40 (ds, 6H), 1.95-2.02 (m, 1H). LC / MS: 440.0 [M + H] +.

Ejemplo 41: Preparacion de [(S)-1-(2-hidroxietil)-2-oxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 41: Preparation of [(S) -1- (2-hydroxyethyl) -2-oxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole - (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic

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Preparacion de (S)-3-Amino-1-(2-hidroxi-etil)-pirrolidin-2-onaPreparation of (S) -3-Amino-1- (2-hydroxy-ethyl) -pyrrolidin-2-one

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Se anadio NaBH4 (85 mg, 2,24 mmol) a una solucion de 40b (160 mg, 0,56 mmol) en alcohol terc-butilico (5 ml). La temperatura se llevo a 80 °C y se anadio lentamente MeOH (0,6 ml). La mezcla resultante se mantuvo a reflujo durante 2 h. Despues de enfriar en un bano de hielo, se anadio H2O (20 ml) y los alcoholes se evaporaron al vado. La fase acuosa se extrajo con AE varias veces. La capa organica se seco sobre MgSO4 anhidro y se concentro. El residuo se purifico por TLC prep. para proporcionar 41a (38 mg). A una solucion del compuesto 41a (38 mg, 0,156 mmol) en 5 ml de DCM se le anadio TFA (0,18 ml, 2,34 mmol). La mezcla resultante se agito a t.a. durante aproximadamente 1 h y se evaporo. El residuo se anadio a una solucion de A4 (36 mg, 0,086 mmol) y DIEA (0,08 ml, 0,43 mmol) en 20 ml de DMF. La mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (5 ml). El precipitado se recogio por filtracion, se lavo con etanol y se seco al vado para dar un solido de color naranja (29 mg, rendimiento del 79,2 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,69(s, 1H), 10,91 (s, 1H), 7,72-7,85(m, 3H), 6,82-6,96(m, 2H), 4,58-4,74(m,2H), 3,37- 3,54(m, 4H), 3,12-3,20(m, 1H), 1,87-2,45(m, 8H), 1,23-1,97(m, 1H). CL/EM: 427,0 [M+H]+.NaBH4 (85 mg, 2.24 mmol) was added to a solution of 40b (160 mg, 0.56 mmol) in tert-butyl alcohol (5 ml). The temperature was brought to 80 ° C and MeOH (0.6 ml) was added slowly. The resulting mixture was refluxed for 2 h. After cooling in an ice bath, H2O (20 ml) was added and the alcohols evaporated to the ford. The aqueous phase was extracted with EA several times. The organic layer was dried over anhydrous MgSO4 and concentrated. The residue was purified by prep TLC. to provide 41a (38 mg). To a solution of compound 41a (38 mg, 0.156 mmol) in 5 ml of DCM was added TFA (0.18 ml, 2.34 mmol). The resulting mixture was stirred at t.a. for about 1 h and evaporated. The residue was added to a solution of A4 (36 mg, 0.086 mmol) and DIEA (0.08 ml, 0.43 mmol) in 20 ml of DMF. The reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (5 ml). The precipitate was collected by filtration, washed with ethanol and dried in vacuo to give an orange solid (29 mg, 79.2% yield): 1 H NMR (300 MHz, DMSO-d6): 5 = 13, 69 (s, 1H), 10.91 (s, 1H), 7.72-7.85 (m, 3H), 6.82-6.96 (m, 2H), 4.58-4.74 ( m, 2H), 3.37-3.54 (m, 4H), 3.12-3.20 (m, 1H), 1.87-2.45 (m, 8H), 1.23-1, 97 (m, 1 H). LC / MS: 427.0 [M + H] +.

Ejemplo 42: Preparacion de [(R)-2-(2-hidroxietil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxilicoExample 42: Preparation of [(R) -2- (2-hydroxyethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole - (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic

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Preparacion de ((R)-3-oxo-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxilico (42b)Preparation of ((R) -3-oxo-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4 - dimethyl-1 H-pyrrole-3-carboxylic (42b)

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A la solucion de A4 (1,75 g, 4,2 mmol) y DIEA (2,5 g, 17 mmol) en 150 ml de DMF se le anadio el compuesto 42a (800 mg, 5,1 mmol). La mezcla de reaccion se agito a temperatura ambiente durante varias horas. El analisis por CL/EM se aplico para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (500 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol y se seco al vado para proporcionar para proporcionar 42b (1,41 g, rendimiento del 87,6 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,88(s,1H), 7,71-7,77(m, 3H), 7,41(s, 1H), 6,82-6,96(m, 2H), 4,08-4,13(m, 1H), 3,06-3,13(m, 1H), 2,41-2,45(ds, 6H), 2,25-2,31(m, 2H), 1,79-1,98(m, 3H). CL/EM: 395,3 [M-H]+.To the solution of A4 (1.75 g, 4.2 mmol) and DIEA (2.5 g, 17 mmol) in 150 ml of DMF compound 42a (800 mg, 5.1 mmol) was added. The reaction mixture was stirred at room temperature for several hours. The LC / MS analysis was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (500 ml) with sonication. The solid was collected by filtration, washed with methanol and dried in vacuo to provide to provide 42b (1.41 g, 87.6% yield): 1 H NMR (300 MHz, DMSO-d6): 5 = 13, 68 (s, 1H), 10.88 (s, 1H), 7.71-7.77 (m, 3H), 7.41 (s, 1H), 6.82-6.96 (m, 2H) , 4.08-4.13 (m, 1H), 3.06-3.13 (m, 1H), 2.41-2.45 (ds, 6H), 2.25-2.31 (m, 2H), 1.79-1.98 (m, 3H). LC / MS: 395.3 [M-H] +.

A la solucion de 42b (1,0 equiv.) enfriada en un bano de hielo se le anadio NaH (4,0 o 1,5 equiv.). La mezcla resultante se agito durante una hora y despues se anadio 2-bromoetanol (3 equiv.), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol con sonicacion. El solido se recogio por filtracion, se lavo dos veces con metanol, y se purifico adicionalmente por CL prep. para obtener el compuesto del tftulo (18 mg, rendimiento del 11 %) en forma de solidos de color naranja: RMN 1H (300 MHz, DMSO-d6): 5 = 13,70(s, 1H), 10,91 (s, 1H), 8,08-8,10(d, 1H), 7,72-7,79(m, 2H), 6,82-6,97(m, 2H), 5,01-5,10(c, 1H), 4,79-4,81(t, 1H), 4,56-4,62(t, 1H), 4,02-4,08(c, 1H), 3,49-3,63(m, 4H), 2,41-2,43(ds, 6H). CL/EM: 428,9 [M+H]+.To the solution of 42b (1.0 equiv.) Cooled in an ice bath was added NaH (4.0 or 1.5 equiv.). The resulting mixture was stirred for one hour and then 2-bromoethanol (3 equiv.) Was added, and the reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol with sonication. The solid was collected by filtration, washed twice with methanol, and further purified by prep CL. to obtain the title compound (18 mg, 11% yield) as orange solids: 1 H NMR (300 MHz, DMSO-d6): 5 = 13.70 (s, 1 H), 10.91 (s , 1H), 8.08-8.10 (d, 1H), 7.72-7.79 (m, 2H), 6.82-6.97 (m, 2H), 5.01-5.10 (c, 1H), 4.79-4.81 (t, 1H), 4.56-4.62 (t, 1H), 4.02-4.08 (c, 1H), 3.49-3 , 63 (m, 4H), 2.41-2.43 (ds, 6H). LC / MS: 428.9 [M + H] +.

Ejemplo 43: Preparacion de ((R)-2-dimetilcarbamoilmetil-3-oxo-isoxazolidin-4-il)-amida del acido 5-[5-fluoro- 2-oxo-1,2-dihidra-mdol-(3Z)-iMdenmetM]-2,4-dimetiMH-pirral-3-carboxiMcoExample 43: Preparation of ((R) -2-dimethylcarbamoylmethyl-3-oxo-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydra-mdol- (3Z) -iMdenmetM] -2,4-dimetiMH-pyrral-3-carboxyMco

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A la solucion de 42b (1,0 equiv.) enfriada en un bano de hielo se le anadio NaH (4,0 o 1,5 equiv.). La mezcla resultante se agito durante una hora y despues se anadio 2-bromo-N,N-dimetilacetamida (1,0 equiv.), y la mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol con sonicacion. El solido se recogio por filtracion, se lavo dos veces con metanol, y se purifico adicionalmente por cromatograffa en columna para obtener el compuesto del tftulo (30 mg, rendimiento del 13,6 %) en forma de solidos de color naranja: RMN 1H (300 MHz, DMSO-d6): 5 = 13,73(s, 1H), 10,93(s, 1H), 8,05-8,08(d, 1H), 7,74-7,80(m, 2H), 6,82-6,97(m, 2H), 5,06-5,15(c, 1H), 4,39-4,58(m, 3H), 4,05-4,11 (c, 1H), 2,97(s, 3H), 2,84(s, 3H), 2,44-2,47(ds, 6H). CL/EM: 468,2 [M-H]+.To the solution of 42b (1.0 equiv.) Cooled in an ice bath was added NaH (4.0 or 1.5 equiv.). The resulting mixture was stirred for one hour and then 2-bromo-N, N-dimethylacetamide (1.0 equiv.) Was added, and the reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol with sonication. The solid was collected by filtration, washed twice with methanol, and further purified by column chromatography to obtain the title compound (30 mg, 13.6% yield) as orange solids: 1 H NMR ( 300 MHz, DMSO-d6): 5 = 13.73 (s, 1H), 10.93 (s, 1H), 8.05-8.08 (d, 1H), 7.74-7.80 (m , 2H), 6.82-6.97 (m, 2H), 5.06-5.15 (c, 1H), 4.39-4.58 (m, 3H), 4.05-4.11 (c, 1H), 2.97 (s, 3H), 2.84 (s, 3H), 2.44-2.47 (ds, 6H). LC / MS: 468.2 [M-H] +.

Ejemplo 44: Preparacion de ((R)-2-etil-3-oxo-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- mdol-(3Z)-ilidenmetM]-2,4-dimetiMH-pirrol-3-carboxflicoExample 44: Preparation of ((R) -2-ethyl-3-oxo-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ilidenmetM] -2,4-dimetiMH-pyrrole-3-carboxylic

imagen60image60

Preparacion de (R)-4-Amino-2-etil-isoxazolidin-3-onaPreparation of (R) -4-Amino-2-ethyl-isoxazolidin-3-one

imagen61image61

Etapa 1: El compuesto 42a (500 mg, 4,9 mmol) y TEA (976 mg, 9,64 mmol) se disolvieron en una mezcla de THF/agua (85 ml, V/V 10:7). Se anadio gota a gota (Boc)2O (1,17 g, 5,4 mmol) en refrigeracion con hielo. DespuesStep 1: Compound 42a (500 mg, 4.9 mmol) and TEA (976 mg, 9.64 mmol) were dissolved in a mixture of THF / water (85 ml, V / V 10: 7). (Boc) 2O (1.17 g, 5.4 mmol) was added dropwise under ice cooling. After

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45Four. Five

de que se completase la adicion, la mezcla se calento a t.a. y se agito durante 5 h. La mezcla se evaporo a sequedad y el residuo se purifico por cromatografia en columna (AE:PE = 3:1) para proporcionar el compuesto 44a (600 mg, 61 %) en forma de un solido de color blanco.Upon completion of the addition, the mixture was heated to t.a. and stirred for 5 h. The mixture was evaporated to dryness and the residue was purified by column chromatography (EA: PE = 3: 1) to give compound 44a (600 mg, 61%) as a white solid.

Etapa 2: A la solucion del compuesto 44a (100 mg, 0,5 mmol) se le anadio NaH al 60 % (24 mg, 0,6 mmol) en refrigeracion con hielo. La mezcla resultante se agito durante 1 h y se anadio bromoetano (60 mg, 0,55 mmol). La mezcla se calento a t.a. y se agito durante una noche y se evaporo a sequedad. El residuo se purifico por cromatografia en columna (AE:PE = 10:1) para proporcionar el compuesto 44b (109 mg, 94,7 %).Step 2: To the solution of compound 44a (100 mg, 0.5 mmol) was added 60% NaH (24 mg, 0.6 mmol) in ice cooling. The resulting mixture was stirred for 1 h and bromoethane (60 mg, 0.55 mmol) was added. The mixture was heated to t.a. and stirred overnight and evaporated to dryness. The residue was purified by column chromatography (EA: PE = 10: 1) to provide compound 44b (109 mg, 94.7%).

Etapa 3: A una solucion del compuesto 44b (109 mg, 0,47 mmol) en 5 ml de DCM se le anadio TFA (810 mg,Step 3: To a solution of compound 44b (109 mg, 0.47 mmol) in 5 ml of DCM was added TFA (810 mg,

7,1 mmol). La mezcla resultante se agito a t.a. durante aproximadamente 1 h y se evaporo, que despues se anadio a la solucion de A4 (160 mg, 0,38 mmol) y DIEA (196 mg, 1,52 mmol) en 18 ml de dMf. La mezcla de reaccion se agito a temperatura ambiente durante varias horas. Se aplico deteccion por CL/EM para determinar la finalizacion de la reaccion. Se evaporo la DMF a presion reducida y el residuo se precipito con dietilamina al 5 %/metanol (10 ml) con sonicacion. El solido se recogio por filtracion, se lavo con metanol y se seco al vado para proporcionar el compuesto del fitulo (123 mg, rendimiento del 77,8 %). RMN 1H (300 MHz, DMSO-d6): 5 = 13,71(s, 1h),10,39(s, 1H), 8,07-8,10(d, 1H), 7,72-7,78(m, 2H), 6,82-6,96(m, 2H), 4,97-5,06(c, 1H), 4,57-4,62(t, 1H), 4,02-4,08(c, 1H), 3,50- 3,58(m, 2H), 2,43-2,45(ds,6H), 1,13-1,18(t,3H). CL/EM: 412,9 [M+H]+.7.1 mmol). The resulting mixture was stirred at t.a. for about 1 h and it was evaporated, which was then added to the solution of A4 (160 mg, 0.38 mmol) and DIEA (196 mg, 1.52 mmol) in 18 ml of dMf. The reaction mixture was stirred at room temperature for several hours. CL / MS detection was applied to determine the completion of the reaction. The DMF was evaporated under reduced pressure and the residue was precipitated with 5% diethylamine / methanol (10 ml) with sonication. The solid was collected by filtration, washed with methanol and dried in vacuo to provide the phyto compound (123 mg, 77.8% yield). 1H NMR (300 MHz, DMSO-d6): 5 = 13.71 (s, 1h), 10.39 (s, 1H), 8.07-8.10 (d, 1H), 7.72-7, 78 (m, 2H), 6.82-6.96 (m, 2H), 4.97-5.06 (c, 1H), 4.57-4.62 (t, 1H), 4.02- 4.08 (c, 1H), 3.50-3.58 (m, 2H), 2.43-2.45 (ds, 6H), 1.13-1.18 (t, 3H). LC / MS: 412.9 [M + H] +.

Ejemplo 45: Preparacion de ((R)-2-carbamoilmetil- 3-oxo-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-Example 45: Preparation of ((R) -2-carbamoylmethyl-3-oxo-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-

1,2-dihidre-mdol-(3Z)-iNdenmetM]-2,4-dimetiMH-pirrel-3-carboxfiico1,2-dihydre-mdol- (3Z) -iNdenmetM] -2,4-dimetiMH-pyrrel-3-carboxylic

imagen62image62

La smtesis del compuesto del fitulo es similar a la del Ejemplo 44 (rendimiento 71 %)): RMN 1H (300 MHz, DMSO- d6): 5 = 13,73(s, 1H), 10,91(s, 1H), 8,09-8,11(d, 1H), 7,73-7,79(m, 2H), 7,33-7,53(ds, 2H), 6,82-6,97(m, 2H), 5,02- 5,07(c, 1H), 4,55-4,60(t, 1H), 4,01-4,17(m, 3H), 2,44-2,46(ds,6H). CL/EM: 441,9 [M+H]+.The synthesis of the phyto compound is similar to that of Example 44 (71% yield): 1 H NMR (300 MHz, DMSO-d6): 5 = 13.73 (s, 1 H), 10.91 (s, 1 H) , 8.09-8.11 (d, 1H), 7.73-7.79 (m, 2H), 7.33-7.53 (ds, 2H), 6.82-6.97 (m, 2H), 5.02- 5.07 (c, 1H), 4.55-4.60 (t, 1H), 4.01-4.17 (m, 3H), 2.44-2.46 ( ds, 6H). LC / MS: 441.9 [M + H] +.

Ejemplo 46: Preparacion de [(R)-2-(2-metoxi-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo- 1,2-dihidre-mdol-(3Z)-iNdenmetM]-2,4-dimetiMH-pirrel-3-carboxfiicoExample 46: Preparation of [(R) -2- (2-methoxy-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydre -mdol- (3Z) -iNdenmetM] -2,4-dimetiMH-pyrrel-3-carboxyphic

imagen63image63

La smtesis del compuesto del fitulo es similar a la del Ejemplo 44 (rendimiento del 89,3 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,75(s, 1H), 10,91(s,1H), 8,09-8,12(d, 1H), 7,72-7,79(m, 2H), 6,82-6,97(m, 2H), 4,99-5,08(c, 1H), 4,57-4,63(t, 1H), 4,01-4,07(c, 1H), 3,37-3,74(m, 4H),3,22(s, 3H), 2,35-2,37(ds, 6H). CL/EM: 443,0 [M+H]+.The synthesis of the phytic compound is similar to that of Example 44 (89.3% yield): 1H NMR (300 MHz, DMSO-d6): 5 = 13.75 (s, 1H), 10.91 (s, 1H), 8.09-8.12 (d, 1H), 7.72-7.79 (m, 2H), 6.82-6.97 (m, 2H), 4.99-5.08 ( c, 1H), 4.57-4.63 (t, 1H), 4.01-4.07 (c, 1H), 3.37-3.74 (m, 4H), 3.22 (s, 3H), 2.35-2.37 (ds, 6H). LC / MS: 443.0 [M + H] +.

Ejemplo 47: Preparacion de ((R)-3-oxo-2-piridin-3-ilmetil-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo- 1,2-dihidre-mdol-(3Z)-iNdenmetM]-2,4-dimetiMH-pirrel-3-carboxfiicoExample 47: Preparation of ((R) -3-oxo-2-pyridin-3-ylmethyl-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydre-mdol - (3Z) -iNdenmetM] -2,4-dimetiMH-pyrrel-3-carboxylic

imagen64image64

La smtesis del compuesto del fitulo es similar a la del Ejemplo 44 (rendimiento del 73,8 %): RMN 1H (300 MHz, DMSO-d6): 5 = 13,73(s, 1H), 10,91(s, 1H), 8,52-8,57(m, 2H), 8,17-8,19(d, 1H), 7,73-7,79(m, 3H), 7,39-7,43(m, 1H),The synthesis of the phyto compound is similar to that of Example 44 (73.8% yield): 1H NMR (300 MHz, DMSO-d6): 5 = 13.73 (s, 1H), 10.91 (s, 1H), 8.52-8.57 (m, 2H), 8.17-8.19 (d, 1H), 7.73-7.79 (m, 3H), 7.39-7.43 ( m, 1H),

6,82-6,97(m, 2H), 5,05-5,14(c, 1H), 4,63-4,85(c, 2H), 4,57-4,63(t, 1H), 4,06-4,13(c, 1H), 2,43-2,46(ds, 6H). CL/EM:6.82-6.97 (m, 2H), 5.05-5.14 (c, 1H), 4.63-4.85 (c, 2H), 4.57-4.63 (t, 1H ), 4.06-4.13 (c, 1H), 2.43-2.46 (ds, 6H). LC / MS:

476,1 [M+H]+.476.1 [M + H] +.

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Preparacion de (R)-4-Amino-2-(tetrahidro-piran-4-il)-isoxazolidin-3-ona (48c)Preparation of (R) -4-Amino-2- (tetrahydro-pyran-4-yl) -isoxazolidin-3-one (48c)

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44a 48a 48b 48c44a 48a 48b 48c

Etapa 1: A una solucion de 44a (150 mg, 0,74 mmol), 48a (83 mg, 0,82 mmol) y PPh3 (290 mg, 1,1 mmol) en THF (20 ml) se le anadio gota a gota DEAD (206 mg, 1,2 mmol) en THF (2 ml) a -60 °C. Despues de que se completase la adicion, la mezcla de reaccion se calento a temperatura ambiente gradualmente y se agito durante 2 dias. Despues, la mezcla se evaporo y el residuo se purifico por cromatografia en columna (AE:PE = 4:1) para proporcionar un aceite transparente que aun contenia una pequena cantidad de 44a. El aceite obtenido se purifico de nuevo por TLC prep. para proporcionar una mezcla de 48b y POPh3 (131 mg).Step 1: To a solution of 44a (150 mg, 0.74 mmol), 48a (83 mg, 0.82 mmol) and PPh3 (290 mg, 1.1 mmol) in THF (20 ml) was added dropwise to DEAD drop (206 mg, 1.2 mmol) in THF (2 ml) at -60 ° C. After the addition was completed, the reaction mixture was gradually heated to room temperature and stirred for 2 days. Then, the mixture was evaporated and the residue was purified by column chromatography (EA: PE = 4: 1) to provide a clear oil that still contained a small amount of 44a. The oil obtained was purified again by prep TLC. to provide a mixture of 48b and POPh3 (131 mg).

Etapa 2: A una solucion de la mezcla obtenida de 48b y POPh3 (131 mg) en DCM (4 ml) se le anadio TFA (1 ml) a temperatura ambiente. La mezcla se agito durante 3 h y se evaporo para proporcionar 48c en bruto que se uso en la siguiente etapa directamente.Step 2: To a solution of the mixture obtained from 48b and POPh3 (131 mg) in DCM (4 ml), TFA (1 ml) was added at room temperature. The mixture was stirred for 3 h and evaporated to provide 48c crude which was used in the next step directly.

Etapa 3: A una solucion de A4 (84 mg, 2 mmol) en 10 ml de DMF se le anadieron 48c en bruto de la ultima etapa y DIEA (2 ml), y la mezcla de reaccion se agito a temperatura ambiente durante una noche. El analisis por CL/EM se aplico para determinar la finalizacion de la reaccion. La mezcla de reaccion se evaporo a presion reducida y el residuo se trituro con dietilamina al 5 %/metanol (25 ml). El solido se recogio por filtracion, se lavo con metanol y se seco al vacio para proporcionar el compuesto del titulo (58 mg, 62 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,73(s, 1H), 10,94(s, 1H), 8,12-8,15(d, 1H), 7,73-7,80(m, 2H), 6,82-6,87(m, 2H), 5,02- 5,05(c, 1H), 4,58-4,64(t, 1H), 3,86-4,14(m, 4H),3,38-3,44(m, 2H), 2,42-2,50(ds, 6H), 1,65-1,88(m, 4H). CL/EM: 469,0 [M+H]+.Stage 3: To a solution of A4 (84 mg, 2 mmol) in 10 ml of DMF was added 48c crude from the last stage and DIEA (2 ml), and the reaction mixture was stirred at room temperature overnight . The LC / MS analysis was applied to determine the completion of the reaction. The reaction mixture was evaporated under reduced pressure and the residue was triturated with 5% diethylamine / methanol (25 ml). The solid was collected by filtration, washed with methanol and dried in vacuo to provide the title compound (58 mg, 62%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.73 (s, 1H), 10.94 (s, 1H), 8.12-8.15 (d, 1H), 7.73-7, 80 (m, 2H), 6.82-6.87 (m, 2H), 5.02-5.05 (c, 1H), 4.58-4.64 (t, 1H), 3.86- 4.14 (m, 4H), 3.38-3.44 (m, 2H), 2.42-2.50 (ds, 6H), 1.65-1.88 (m, 4H). LC / MS: 469.0 [M + H] +.

Ejemplo 49: Preparacion de [(R)-3-oxo-2-(tetrahidro-furan-3-il)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2- oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxllicoExample 49: Preparation of [(R) -3-oxo-2- (tetrahydro-furan-3-yl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2- oxo-1,2 -dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic acid

imagen67image67

Preparacion de (R)-4-Amino-2-(tetrahidro-furan-3-il)-isoxazolidin-3-ona (49c)Preparation of (R) -4-Amino-2- (tetrahydro-furan-3-yl) -isoxazolidin-3-one (49c)

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44a 49a 49b 49c44a 49a 49b 49c

La sintesis fue similar a la del Ejemplo 48 excepto que se uso el compuesto 49a. El compuesto del titulo (59 mg, 65 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,94(s, 1H), 8,12-8,15(d, 1H), 7,73-7,80(m, 2H), 6,82-6,97(m, 2H), 4,99-5,05(c, 1H), 4,58-4,78(m, 2H), 4,03-4,10(m, 1H), 3,69-3,88(m, 4H), 2,13-2,40(ds, 6H), 2,03-2,13(m, 4H). CL/EM: 454,9 [M+H]+.The synthesis was similar to that of Example 48 except that compound 49a was used. The title compound (59 mg, 65%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.94 (s, 1H), 8.12-8.15 (d, 1H), 7.73-7, 80 (m, 2H), 6.82-6.97 (m, 2H), 4.99-5.05 (c, 1H), 4.58-4.78 (m, 2H), 4.03- 4.10 (m, 1H), 3.69-3.88 (m, 4H), 2.13-2.40 (ds, 6H), 2.03-2.13 (m, 4H). LC / MS: 454.9 [M + H] +.

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Preparacion de (4-Amino-piperidin-1-il)-morfolin-4-il-metanona (50d):Preparation of (4-Amino-piperidin-1-yl) -morpholin-4-yl-methanone (50d):

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Etapa 1: A una solucion de morfolina (20 g, 0,23 mol), piridina (31 ml, 0,38 mol) en DCM (100 ml) se le anadio gota a gota clorooato de etilo (27,4 g, 0,253 mol) a 0 °C. La mezcla obtenida se agito a temperatura ambiente durante una noche y se lavo con NaHCO3 acuoso saturado y salmuera. La fase organica se seco sobre Na2SO4 anhidro y se evaporo para proporcionar 50a en bruto (36 g, 96 %) en forma de un solido de color amarillo.Step 1: To a solution of morpholine (20 g, 0.23 mol), pyridine (31 ml, 0.38 mol) in DCM (100 ml), ethyl chloroate (27.4 g, 0.253 was added dropwise) mol) at 0 ° C. The obtained mixture was stirred at room temperature overnight and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4 and evaporated to give 50a crude (36 g, 96%) as a yellow solid.

Etapa 2: Una mezcla de 50a (20 g, 0,126 mol) y POCh (97 g, 0,63 mol) en ACN seco (200 ml) se calento a reflujo durante 18 h con agitacion. Despues de enfriarse, la mezcla de reaccion se diluyo con DCM (80 ml) y se vertio en hielo picado. La capa organica se separo y la capa acuosa se extrajo por DCM (200 ml x 3). La fase DCM combinada se lavo con NaHCO3 acuoso saturado y salmuera, se seco sobre Na2SO4 anhidro y se evaporo. El residuo se purifico por destilacion. El compuesto 50b se obtuvo recogiendo el destilado de 82 °C-84 °C (1 mmHg) (13 g, 69 %).Stage 2: A mixture of 50a (20 g, 0.126 mol) and POCh (97 g, 0.63 mol) in dry ACN (200 ml) was heated at reflux for 18 h with stirring. After cooling, the reaction mixture was diluted with DCM (80 ml) and poured into crushed ice. The organic layer was separated and the aqueous layer was extracted by DCM (200 ml x 3). The combined DCM phase was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4 and evaporated. The residue was purified by distillation. Compound 50b was obtained by collecting the 82 ° C-84 ° C (1 mmHg) distillate (13 g, 69%).

Etapa 3: A una solucion de 6a (20 g, 0,23 mol), TEA (31 ml, 0,38 mol) en DCM (100 ml) se le anadio gota a gota 50b (27,4 g, 0,253 mol) en DCM a 0 °C. La mezcla obtenida se agito a temperatura ambiente durante una noche y se lavo con NaHCO3 acuoso saturado y salmuera. La fase organica se seco sobre Na2SO4 anhidro y se evaporo para proporcionar 50c en bruto (77 mg, 95 %) en forma de un solido de color amarillo.Step 3: To a solution of 6a (20 g, 0.23 mol), TEA (31 ml, 0.38 mol) in DCM (100 ml) 50b (27.4 g, 0.253 mol) was added dropwise in DCM at 0 ° C. The obtained mixture was stirred at room temperature overnight and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4 and evaporated to give 50c crude (77 mg, 95%) as a yellow solid.

La etapa de-Boc y el acoplamiento final a A4 fueron similares a los del ejemplo 48 para obtener el compuesto del tftulo (45 mg, 60 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,90(s, 1H), 7,59-7,78(m, 3H), 6,81-6,93(m, 2H), 3,91-3,94(m, 1H), 3,56-3,60(m, 6H), 3,11-3,13(m, 4H), 2,83-2,91(t, 2H), 2,39-2,41 (ds, 6H), 1,79-1,1,83(m, 2H), 1,44-1,51(m, 2H). CL/EM: 496,0 [M+H]+.The de-Boc step and the final coupling to A4 were similar to those in example 48 to obtain the title compound (45 mg, 60%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.90 (s, 1H), 7.59-7.78 (m, 3H), 6.81-6, 93 (m, 2H), 3.91-3.94 (m, 1H), 3.56-3.60 (m, 6H), 3.11-3.13 (m, 4H), 2.83- 2.91 (t, 2H), 2.39-2.41 (ds, 6H), 1.79-1.1.83 (m, 2H), 1.44-1.51 (m, 2H). LC / MS: 496.0 [M + H] +.

Ejemplo 51: Preparacion de [(S)-l-(morfolina- 4-carbonil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-mdol-(3Z)-iMdenmetM]-2,4-dimetiMH-pirrol-3-carboxiMcoExample 51: Preparation of [(S) -l- (morpholine-4-carbonyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- ( 3Z) -iMdenmetM] -2,4-dimetiMH-pyrrole-3-carboxyMco

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Preparacion de ((R)-3-Amino-pirrolidin-1-il)-morfolin-4-il-metanona (51c):Preparation of ((R) -3-Amino-pyrrolidin-1-yl) -morpholin-4-yl-methanone (51c):

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50b 51b 51c50b 51b 51c

La smtesis fue similar a la del Ejemplo 50 excepto que se uso el compuesto 51a. El compuesto del tftulo (83 mg, 79 %) se obtuvo finalmente en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,90(s, 1H), 7,72-7,84(m, 3H), 6,82-6,93(m, 2H), 4,31-4,33(m, 1H), 3,48-3,58(m, 6H), 3,24-3,34(m, 2H), 3,13- 3,16(m, 4H), 2,38-2,40(ds, 6H), 1,87-2,03(m, 2H). CL/EM: 480,3 [M-H]+.The synthesis was similar to that of Example 50 except that compound 51a was used. The title compound (83 mg, 79%) was finally obtained in the form of an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.90 (s, 1H), 7.72-7.84 (m, 3H), 6.82-6, 93 (m, 2H), 4.31-4.33 (m, 1H), 3.48-3.58 (m, 6H), 3.24-3.34 (m, 2H), 3.13- 3.16 (m, 4H), 2.38-2.40 (ds, 6H), 1.87-2.03 (m, 2H). LC / MS: 480.3 [M-H] +.

Ejemplo 52: Preparacion de dimetilamida del acido 4-({5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carbonil}-amino)-piperidina-1-carboxflicoExample 52: Preparation of dimethylamide of acid 4 - ({5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3- carbonyl} -amino) -piperidine-1-carboxylic

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El compuesto del trtulo (35 mg, 56 %) se obtuvo en forma de un solido de color naranja siguiendo el procedimiento para el Ejemplo 50. RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,91(s, 1H), 7,60-7,79(m, 3H), 6,81-6,96(m, 2H), 3,90-3,92(m, 1H), 3,50-3,54(d, 2H), 2,77-2,84(t, 2H), 3,13-3,16(m, 4H), 2,73(s, 6H), 2,39-2,41(ds, 6H), 1,78- 1,82(m, 2H), 1,45-1,52(m, 2H). CL/EM: 452,3 [M-H]+.The title compound (35 mg, 56%) was obtained as an orange solid following the procedure for Example 50. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H) , 10.91 (s, 1H), 7.60-7.79 (m, 3H), 6.81-6.96 (m, 2H), 3.90-3.92 (m, 1H), 3 , 50-3.54 (d, 2H), 2.77-2.84 (t, 2H), 3.13-3.16 (m, 4H), 2.73 (s, 6H), 2.39 -2.41 (ds, 6H), 1.78-1.82 (m, 2H), 1.45-1.52 (m, 2H). LC / MS: 452.3 [M-H] +.

Ejemplo 53: Preparacion de ((S)-1-dimetilcarbamoil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 53: Preparation of ((S) -1-dimethylcarbamoyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2,4-dimethyl-1H-pyrrole-3-carboxMico

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El compuesto del titulo (20 mg, 55 %) se obtuvo en forma de un solido de color naranja siguiendo el procedimiento para el Ejemplo 51. RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,91(s, 1H), 7,72-7,83(m, 3H), 6,82-6,96(m, 2H), 4,28-4,36(m, 1H), 3,21-3,53(m, 4H), 2,73(s, 6H), 2,38-2,40(ds, 6H), 1,85-2,04(m, 2H). CL/EM: 438,3 [M-H]+.The title compound (20 mg, 55%) was obtained as an orange solid following the procedure for Example 51. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H) , 10.91 (s, 1H), 7.72-7.83 (m, 3H), 6.82-6.96 (m, 2H), 4.28-4.36 (m, 1H), 3 , 21-3.53 (m, 4H), 2.73 (s, 6H), 2.38-2.40 (ds, 6H), 1.85-2.04 (m, 2H). LC / MS: 438.3 [M-H] +.

Ejemplo 54: Preparacion de [1-(2-metoxiacetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- mdol-(3Z)-ilidenmetN]-2,4-dimetiMH-pirrol-3-carboxflicoExample 54: Preparation of [1- (2-methoxyacetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmetN] - 2,4-dimetiMH-pyrrole-3-carboxylic

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Preparacion de 1-(4-Amino-piperidin-1-il)-2-metoxi-etanona (54d):Preparation of 1- (4-Amino-piperidin-1-yl) -2-methoxy-ethanone (54d):

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54a 54b 54c 54d54a 54b 54c 54d

Etapa 1: A una solucion del compuesto 54a (20 ml, 0,26 mol) en DCM (170 ml) a 0 °C se le anadio gota a gota cloruro de oxalilo (30 ml, 0,34 mol) y unas gotas de DMF. La mezcla se agito a temperatura ambiente durante una noche y se evaporo. El residuo se destilo para proporcionar 54b (25,4 g, 90 %).Step 1: To a solution of compound 54a (20 ml, 0.26 mol) in DCM (170 ml) at 0 ° C was added dropwise oxalyl chloride (30 ml, 0.34 mol) and a few drops of DMF The mixture was stirred at room temperature overnight and evaporated. The residue was distilled to provide 54b (25.4 g, 90%).

Etapa 2: A una solucion de 6a (100 mg, 0,5 mmol) y TEA (0,16 ml, 2 mmol) en DCM (10 ml) se le anadio gota a gota 54b (60 mg, 0,55 mmol) en dCm (2 ml) a 0 °C. La mezcla obtenida se agito a temperatura ambiente durante una noche y se lavo con NaHCO3 acuoso saturado y salmuera. La fase organica se seco sobre Na2SO4 anhidro y se evaporo para proporcionar 54c en bruto (129 mg, 95 %) en forma de un solido de color amarillo.Step 2: To a solution of 6a (100 mg, 0.5 mmol) and TEA (0.16 ml, 2 mmol) in DCM (10 ml) 54b (60 mg, 0.55 mmol) was added dropwise in dCm (2 ml) at 0 ° C. The obtained mixture was stirred at room temperature overnight and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4 and evaporated to give crude 54c (129 mg, 95%) as a yellow solid.

La etapa de-Boc y el acoplamiento final a A4 fueron similares a los del Ejemplo 48. El compuesto del titulo (65 mg, 41 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,65(s, 1H), 10,87(s, 1H), 7,59-7,76(m, 3H), 6,80-7,94(m, 2H), 3,96-4,23(m, 4H), 3:70-3,76(m, 2H), 3,26(s, 3H), 3,08-3,16(m, 1H), 2,71- 2,87(m, 1H), 2,37-2,40(ds, 6H), 1,83-1,85(m, 2H), 1,33-1,45(m, 2H). CL/EM: 454,9 [M+H]+.The de-Boc step and the final coupling to A4 were similar to those in Example 48. The title compound (65 mg, 41%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.65 (s, 1H), 10.87 (s, 1H), 7.59-7.76 (m, 3H), 6.80-7, 94 (m, 2H), 3.96-4.23 (m, 4H), 3: 70-3.76 (m, 2H), 3.26 (s, 3H), 3.08-3.16 ( m, 1H), 2.71-2.87 (m, 1H), 2.37-2.40 (ds, 6H), 1.83-1.85 (m, 2H), 1.33-1, 45 (m, 2H). LC / MS: 454.9 [M + H] +.

Ejemplo 55: Preparacion de [(S)-1-(2-metoxi-acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 55: Preparation of [(S) -1- (2-methoxy-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- ( 3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxyNico

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El compuesto del titulo (51 mg, 31 %) se obtuvo en forma de un solido de color naranja siguiendo el procedimiento para el Ejemplo 54. RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,88(s, 1H), 7,70-7,89(m, 3H), 6,80-6,94(m, 2H), 4,35-4,43(m, 1H), 3,97-3,99(d, 2H), 3,33-3,67(m, 4H), 3,23(s, 3H), 2,37-2,39(ds, 6H), 1,85-2,15(m, 2H). CL/EM: 440,9 [M+H]+.The title compound (51 mg, 31%) was obtained as an orange solid following the procedure for Example 54. 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H) , 10.88 (s, 1H), 7.70-7.89 (m, 3H), 6.80-6.94 (m, 2H), 4.35-4.43 (m, 1H), 3 , 97-3.99 (d, 2H), 3.33-3.67 (m, 4H), 3.23 (s, 3H), 2.37-2.39 (ds, 6H), 1.85 -2.15 (m, 2H). LC / MS: 440.9 [M + H] +.

Ejemplo 56: Preparacion de N-((3R)oxolan-3-il){5-[(5-fluoro-2-oxo(1H-benzo[d]azolm-3-ilideno))metil]-2,4- dimetilpirrol-3-il}carboxamidaExample 56: Preparation of N - ((3R) oxolan-3-yl) {5 - [(5-fluoro-2-oxo (1H-benzo [d] azolm-3-ylidene)) methyl] -2,4- dimethylpyrrol-3-yl} carboxamide

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La smtesis fue similar a la etapa final del Ejemplo 48 usando (S)-(Tetrahidro-furan-3-il)amina como material de partida. El compuesto del titulo (82 mg, 93 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,91 (s, 1H), 7,72-7,88(m, 3H), 6,83-6,93(m, 2H), 4,21-4,25(m, 1H), 3,53-3,87(m, 4H),The synthesis was similar to the final stage of Example 48 using (S) - (Tetrahydro-furan-3-yl) amine as the starting material. The title compound (82 mg, 93%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.91 (s, 1H), 7.72-7.88 (m, 3H), 6.83-6, 93 (m, 2H), 4.21-4.25 (m, 1H), 3.53-3.87 (m, 4H),

2,39-2,41 (ds, 6H), 2,39-2,41 (m, 1H), 2,09-2,12(m, 1H). CL/EM: 370,1 [M+H]+.2.39-2.41 (ds, 6H), 2.39-2.41 (m, 1H), 2.09-2.12 (m, 1H). LC / MS: 370.1 [M + H] +.

Ejemplo 57: Preparacion de [(R)-2-(2-morfolin-4-il-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2- oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxflicoExample 57: Preparation of [(R) -2- (2-morpholin-4-yl-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2- oxo-1 , 2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic acid

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A una solucion de 42b (200 mg, 0,52 mmol), Nal (78 mg, 0,52 mmol) y DIEA (134 mg, 1,04 mmol) en DMF (25 ml) se le anadio NaH al 60 % (125 mg, 3,13 mmol) a 0 °C. Despues de agitar a temperatura ambiente durante 1 h, a la mezcla se le anadio cloruro de 4-(2-cloroetil)-morfolina (194 mg, 1,05 mmol). La mezcla obtenida se agito durante 48 h a temperatura ambiente. Se uso analisis por CL-eM para detectar la finalizacion de la reaccion. La mezcla se evaporo a presion reducida y el residuo se trituro con dietilamina al 5 %/metanol (25 ml). El solido se recogio por filtracion que se purifico de nuevo por cromatografia en columna (CH2Cl2:MeOH = 20:1) para proporcionar el compuesto del titulo (60 mg, 23 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,59(s, 1H), 11,53(s, 1H), 7,79-8,13(m, 3H), 7,04-7,12(m, 2H), 5,00-5,06(c, 1H), 4,57-4,62(t, 1H), 3,97-4,10(m, 3H), 3,44-3,58(m, 4H), 2,78-2,94(m, 1H), 2,47-2,50(ds, 6H). CL/EM: 498,2 [M+H]+.To a solution of 42b (200 mg, 0.52 mmol), Nal (78 mg, 0.52 mmol) and DIEA (134 mg, 1.04 mmol) in DMF (25 ml) was added 60% NaH ( 125 mg, 3.13 mmol) at 0 ° C. After stirring at room temperature for 1 h, 4- (2-chloroethyl) -morpholine chloride (194 mg, 1.05 mmol) was added to the mixture. The obtained mixture was stirred for 48 h at room temperature. CL-eM analysis was used to detect the completion of the reaction. The mixture was evaporated under reduced pressure and the residue was triturated with 5% diethylamine / methanol (25 ml). The solid was collected by filtration which was purified again by column chromatography (CH2Cl2: MeOH = 20: 1) to provide the title compound (60 mg, 23%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.59 (s, 1H), 11.53 (s, 1H), 7.79-8.13 (m, 3H), 7.04-7, 12 (m, 2H), 5.00-5.06 (c, 1H), 4.57-4.62 (t, 1H), 3.97-4.10 (m, 3H), 3.44- 3.58 (m, 4H), 2.78-2.94 (m, 1H), 2.47-2.50 (ds, 6H). LC / MS: 498.2 [M + H] +.

Ejemplo 58: Preparacion de [(S)-1-(2-metoxietil)-2-oxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxflicoExample 58: Preparation of [(S) -1- (2-methoxyethyl) -2-oxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole - (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic

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Etapa 1: A una solucion de 40a (100 mg, 0,5 mmol) en DMF (5 ml) se le anadio NaH al 60 % (21 mg, 0,53 mmol) a 0 °C. Despues de agitar a temperatura ambiente durante 1 h, a la mezcla se le anadio el compuesto 1-Bromo-2- metoxi-etano (67,5 mg, 0,49 mmol). La mezcla obtenida se agito durante una noche a temperatura ambiente y se evaporo. El residuo se purifico por cromatografia en columna (AE:PE = 1:1) para proporcionar 58a (68 mg, 54 %).Step 1: To a solution of 40a (100 mg, 0.5 mmol) in DMF (5 ml), 60% NaH (21 mg, 0.53 mmol) was added at 0 ° C. After stirring at room temperature for 1 h, the compound 1-Bromo-2-methoxy-ethane (67.5 mg, 0.49 mmol) was added to the mixture. The obtained mixture was stirred overnight at room temperature and evaporated. The residue was purified by column chromatography (EA: PE = 1: 1) to provide 58a (68 mg, 54%).

Etapa 2: La etapa de-Boc y el acoplamiento final a A4 fueron similares a los del Ejemplo 48. El compuesto del titulo (54 mg, 77 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,68(s, 1H), 10,91(s, 1H), 7,72-7,87(m, 3H), 6,82-6,93(m, 2H), 4,59-4,62(c, 2H), 3,38-3,49(m, 6H), 3,30(s, 3H), 2,42-2,45(ds, 6H), 2,15-2,20(m, 1H), 1,90-2,00(m, 1H). CL/EM: 439,3 [M-H]+.Stage 2: The de-Boc stage and the final coupling to A4 were similar to those in Example 48. The title compound (54 mg, 77%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.68 (s, 1H), 10.91 (s, 1H), 7.72-7.87 (m, 3H), 6.82-6, 93 (m, 2H), 4.59-4.62 (c, 2H), 3.38-3.49 (m, 6H), 3.30 (s, 3H), 2.42-2.45 ( ds, 6H), 2.15-2.20 (m, 1H), 1.90-2.00 (m, 1H). LC / MS: 439.3 [M-H] +.

Ejemplo 59: Preparacion de ((S)-2-oxo-1-piridin-4-ilmetil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 59: Preparation of ((S) -2-oxo-1-pyridin-4-ylmethyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole - (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

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La sintesis fue similar a la del Ejemplo 58. El compuesto del titulo (24 mg, 66 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,71(s, 1H), 10,93(s, 1H), 8,53-8,55(m, 1H), 8,00-8,02(d, 1H), 7,73-7,80(m, 2H), 7,30-7,32(d, 2H), 6,82-6,95(m, 2H), 4,40-4,69(m, 3H), 3,28-3,34(m, 2H), 2,44-2,47(ds, 6H). CL/EM:The synthesis was similar to that of Example 58. The title compound (24 mg, 66%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.71 (s, 1H), 10.93 (s, 1H), 8.53-8.55 (m, 1H), 8.00-8, 02 (d, 1H), 7.73-7.80 (m, 2H), 7.30-7.32 (d, 2H), 6.82-6.95 (m, 2H), 4.40- 4.69 (m, 3H), 3.28-3.34 (m, 2H), 2.44-2.47 (ds, 6H). LC / MS:

472,2 [M-H]+.472.2 [M-H] +.

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La smtesis fue similar a la del Ejemplo 58. El compuesto del tftulo (51 mg, 79 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,94(s, 1H), 8,14-8,16(d, 1H), 7,73-7,80(m, 2H),The synthesis was similar to that of Example 58. The title compound (51 mg, 79%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.94 (s, 1H), 8.14-8.16 (d, 1H), 7.73-7, 80 (m, 2H),

6,82-6,94(m, 2H), 5,06-5:10(c, 1H), 4,57-4,63(t, 1H), 4,03-4,12(m, 2H), 3,82-3,87(m, 2H), 3,40-3,42(m, 1H), 3,15- 3,42(m, 4H), 2,42-2,45(ds, 6H), 1,80-1,95(m, 1H), 1,53-1,64(m, 2H), 1,18-1,26(m, 2H). CL/EM: 481,2 [M-H]+.6.82-6.94 (m, 2H), 5.06-5: 10 (c, 1H), 4.57-4.63 (t, 1H), 4.03-4.12 (m, 2H ), 3.82-3.87 (m, 2H), 3.40-3.42 (m, 1H), 3.15-3.42 (m, 4H), 2.42-2.45 (ds , 6H), 1.80-1.95 (m, 1H), 1.53-1.64 (m, 2H), 1.18-1.26 (m, 2H). LC / MS: 481.2 [M-H] +.

Ejemplo 61: Preparacion de [(S)-1-(2-metoxietil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 61: Preparation of [(S) -1- (2-methoxyethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

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Etapa 1: Una solucion de 8a (100 mg, 0,54 mmol), 1-bromo-2-metoxi-etano (89,5 mg, 0,64 mmol), KI (94 mg, 0,56 mmol) y K2CO3 (370 mg, 2,69 mmol) en 15 ml de acetonitrilo se agitaron a reflujo durante 48 h. Despues de enfriarse, la mezcla se filtro y el filtrado se evaporo a sequedad. El residuo se purifico por cromatografia en columna (AE:MeOH = 10:1) para dar 6la (102 mg, 78 %) en forma de un aceite de color amarillo.Stage 1: A solution of 8a (100 mg, 0.54 mmol), 1-bromo-2-methoxy-ethane (89.5 mg, 0.64 mmol), KI (94 mg, 0.56 mmol) and K2CO3 (370 mg, 2.69 mmol) in 15 ml of acetonitrile was stirred at reflux for 48 h. After cooling, the mixture was filtered and the filtrate was evaporated to dryness. The residue was purified by column chromatography (EA: MeOH = 10: 1) to give 6la (102 mg, 78%) as a yellow oil.

Etapa 2: La etapa de-Boc y el acoplamiento final a A4 fueron similares a los del Ejemplo 48. El compuesto del titulo (73 mg, 84 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,65(s, 1H), 10,91(s, 1H), 7,71-7,79(m, 3H), 6,82-6,96(m, 2H), 4,31-4,33(m, 1H), 3,40-3,44(t, 2H), 3,24(s, 3H), 2,82-2,88(m, 1H), 2,53-2,60(m, 5H), 3,39-3,41 (ds, 6H), 2,09-2,12(m, 1H), 1,67-1,71(m, 1H). CL/EM: 427,1 [M+H]+.Stage 2: The de-Boc stage and the final coupling to A4 were similar to those in Example 48. The title compound (73 mg, 84%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.65 (s, 1H), 10.91 (s, 1H), 7.71-7.79 (m, 3H), 6.82-6, 96 (m, 2H), 4.31-4.33 (m, 1H), 3.40-3.44 (t, 2H), 3.24 (s, 3H), 2.82-2.88 ( m, 1H), 2.53-2.60 (m, 5H), 3.39-3.41 (ds, 6H), 2.09-2.12 (m, 1H), 1.67-1, 71 (m, 1 H). LC / MS: 427.1 [M + H] +.

Ejemplo 62: Preparacion de [1-(2-metoxi-etil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- mdol-(3Z)-ilidenmetN]-2,4-dimetiMH-pirrol-3-carboxflicoExample 62: Preparation of [1- (2-methoxy-ethyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmetN ] -2,4-dimetiMH-pyrrole-3-carboxylic

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La smtesis fue similar a la del Ejemplo 61. El compuesto del titulo (71 mg, 76 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,90(s, 1H), 7,54-7,78(m, 3H), 6,81-6,96(m, 2H),The synthesis was similar to that of Example 61. The title compound (71 mg, 76%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.90 (s, 1H), 7.54-7.78 (m, 3H), 6.81-6, 96 (m, 2H),

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3,68-3,72(m, 1H), 3,40-3,44(t, 2H), 3,23(s, 3H), 2,83-2,92(m, 2H), 2,45-2,50(m, 2H), 2,39-2,41(ds, 6H), 2,04-2,11 (t, 2H), 1,76-1,79(m, 2H), 1,46-1,57(m, 2H). CL/EM: 441,1 [M+H]+.3.68-3.72 (m, 1H), 3.40-3.44 (t, 2H), 3.23 (s, 3H), 2.83-2.92 (m, 2H), 2, 45-2.50 (m, 2H), 2.39-2.41 (ds, 6H), 2.04-2.11 (t, 2H), 1.76-1.79 (m, 2H), 1.46-1.57 (m, 2H). LC / MS: 441.1 [M + H] +.

Ejemplo 63: Preparacion de [1-(2-dimetilamino-acetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 63: Preparation of [1- (2-dimethylamino-acetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl ] -2,4-dimethyl-1H-pyrrol-3-carboxyNico

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Etapa 1: El compuesto 63c (125 mg, 60 %) se sintetizo siguiendo el procedimiento en la preparacion de 54c en el Ejemplo 54.Step 1: Compound 63c (125 mg, 60%) was synthesized following the procedure in the preparation of 54c in Example 54.

Etapa 2: A una solucion de 63c (125 mg, 0,45 mmol) en 15 ml de acetonitrilo se le anadieron NH(CH3)2-HCl (110 mg, 1,36 mmol) y DIEA (232 mg, 1,8 mmol) a temperatura ambiente. La mezcla obtenida se agito durante una noche y se evaporo. El residuo se disolvio de nuevo en DCM y se lavo con salmuera. La fase de DCM se separo, se seco sobre Na2SO4 anhidro y se evaporo para proporcionar 63d en bruto que se uso directamente para la siguiente etapa de sintesis (118 mg, 92 %).Step 2: To a solution of 63c (125 mg, 0.45 mmol) in 15 ml of acetonitrile was added NH (CH3) 2-HCl (110 mg, 1.36 mmol) and DIEA (232 mg, 1.8 mmol) at room temperature. The obtained mixture was stirred overnight and evaporated. The residue was dissolved again in DCM and washed with brine. The DCM phase was separated, dried over anhydrous Na2SO4 and evaporated to provide 63d crude which was used directly for the next stage of synthesis (118 mg, 92%).

Etapa 3: La etapa de-Boc y el acoplamiento final a A4 fueron similares a los del Ejemplo 48. El compuesto del titulo (49 mg, 51 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,89(s, 1H), 7,61-7,77(m, 3H), 6,80-6,91 (m, 2H), 4,21-4,25(d, 1H), 3,95-3,99(d, 2H), 3,07-3,18(m, 4H), 2,70- 2,79(m, 2H), 2,38-2,40(ds, 6H), 2,15(s, 6H), 1,79-1,83(m, 2H). CL/EM: 466,3 [M-H]+.Stage 3: The de-Boc stage and the final coupling to A4 were similar to those in Example 48. The title compound (49 mg, 51%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.89 (s, 1H), 7.61-7.77 (m, 3H), 6.80-6, 91 (m, 2H), 4.21-4.25 (d, 1H), 3.95-3.99 (d, 2H), 3.07-3.18 (m, 4H), 2.70- 2.79 (m, 2H), 2.38-2.40 (ds, 6H), 2.15 (s, 6H), 1.79-1.83 (m, 2H). LC / MS: 466.3 [M-H] +.

Ejemplo 64: Preparacion de [(S)-1-(2-dimetilamino-acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 64: Preparation of [(S) -1- (2-dimethylamino-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- ( 3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxyNico

imagen86image86

El compuesto del titulo (44 mg, 47 %) se sintetizo en forma de un solido de color naranja siguiendo el procedimiento del Ejemplo 63. RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,91(s, 1H), 7,71-7,89(m, 3H), 6,81-6,95(m, 2H), 4,35-4,44(m, 1H), 3,57-3,78(m, 4H), 2,99-3,01(d, 2H), 2,38-2,40(ds, 6H), 2,08-2,13(ds, 6H), 1,85-2,04(m, 2H). CL/EM: 452,3 [M-H]+.The title compound (44 mg, 47%) was synthesized in the form of an orange solid following the procedure of Example 63. 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.91 (s, 1H), 7.71-7.89 (m, 3H), 6.81-6.95 (m, 2H), 4.35-4.44 (m, 1H), 3, 57-3.78 (m, 4H), 2.99-3.01 (d, 2H), 2.38-2.40 (ds, 6H), 2.08-2.13 (ds, 6H), 1.85-2.04 (m, 2H). LC / MS: 452.3 [M-H] +.

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Ejemplo 65: Preparacion de [1-(2-hidroxi-etil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxflicoExample 65: Preparation of [1- (2-hydroxy-ethyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl ] -2,4-dimethyl-1H-pyrrole-3-carboxylic

imagen87image87

El compuesto del tftulo (31 mg, 39 %) se sintetizo en forma de un solido de color naranja siguiendo el procedimiento del Ejemplo 62. RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,90(s, 1H), 7,56-7,78(m, 3H), 6,81-6,95(m, 2H),The title compound (31 mg, 39%) was synthesized in the form of an orange solid following the procedure of Example 62. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.90 (s, 1H), 7.56-7.78 (m, 3H), 6.81-6.95 (m, 2H),

4,40-4,46(m, 1H), 3,69-3,73(m, 1H), 3,45-3,50(m, 2H), 2,72-2,84(d, 2H), 2,38-2,40(m, 8H), 1,90-2,20(m, 2H), 1,76- 1,80(m, 2H), 1,24-1,44(m, 2H). CL/EM: 427,2 [M+H]+.4.40-4.46 (m, 1H), 3.69-3.73 (m, 1H), 3.45-3.50 (m, 2H), 2.72-2.84 (d, 2H ), 2.38-2.40 (m, 8H), 1.90-2.20 (m, 2H), 1.76-1.80 (m, 2H), 1.24-1.44 (m , 2H). LC / MS: 427.2 [M + H] +.

Ejemplo 66: Preparacion de [(S)-1-(2-hidroxi-etil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 66: Preparation of [(S) -1- (2-hydroxy-ethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- ( 3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

imagen88image88

El compuesto del titulo (29 mg, 35 %) se sintetizo en forma de un solido de color naranja siguiendo el procedimiento del Ejemplo 61. RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,87(s, 1H), 7,70-7,77(m, 3H), 6,81-6,95(m, 2H), 4,32-4,40(m, 2H), 3,44-3,50(c, 2H), 2,77-2,83(t, 1H), 2,52-2,66(m, 2H), 2,39-2,46(m, 8H), 2,07-2,13(m, 1H), 1,62- 1,69(m, 2H), 0,88-0,97-1,44(m, 1H). CL/EM: 413,2 [M+H]+.The title compound (29 mg, 35%) was synthesized in the form of an orange solid following the procedure of Example 61. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.87 (s, 1H), 7.70-7.77 (m, 3H), 6.81-6.95 (m, 2H), 4.32-4.40 (m, 2H), 3, 44-3.50 (c, 2H), 2.77-2.83 (t, 1H), 2.52-2.66 (m, 2H), 2.39-2.46 (m, 8H), 2.07-2.13 (m, 1H), 1.62-1.69 (m, 2H), 0.88-0.97-1.44 (m, 1H). LC / MS: 413.2 [M + H] +.

Ejemplo 67: Preparacion de (6'-metil-3,4,5,6-tetrahidro-2H-[1,3']bipiridinil-4-il)-amida del acido 5-[5-fluoro-2- oxo-1,2-dihidro-mdol-(3Z)-ilidenmetN]-2,4-dimetiMH-pirrol-3-carboxflicoExample 67: Preparation of (6'-methyl-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-4-yl) -amide of the acid 5- [5-fluoro-2- oxo- 1,2-dihydro-mdol- (3Z) -ylidenmetN] -2,4-dimetiMH-pyrrole-3-carboxylic

imagen89image89

Etapa 1: Se anadieron Pd(dba)3 (18,3 mg, 0,02 mmol), Xantphos (35 mg, 0,06 mmol) y Cs2CO3 (456 g, 1,4 mmol) a 10 ml de 1,4-dioxano bajo la proteccion de N2, y a esta mezcla se le anadieron los compuestos 6a (200 mg, 1 mmol) y 66a (224 mg, 1,3 mmol). La mezcla resultante se calento a 100 °C durante 24 h, se enfrio a temperatura ambiente que se recogio en AE (50 ml) y se lavo con salmuera y agua. La fase organica se seco con MgSO4 anhidro y se concentro a presion reducida para dar un residuo que se purifico por cromatografia en columna (PE:AE = 1:1) para proporcionar el compuesto 66b (159 mg, 55 %).Step 1: Pd (dba) 3 (18.3 mg, 0.02 mmol), Xantphos (35 mg, 0.06 mmol) and Cs2CO3 (456 g, 1.4 mmol) were added to 10 ml of 1.4 -dioxane under the protection of N2, compounds 6a (200 mg, 1 mmol) and 66a (224 mg, 1.3 mmol) were added to this mixture. The resulting mixture was heated at 100 ° C for 24 h, cooled to room temperature which was taken up in EA (50 ml) and washed with brine and water. The organic phase was dried with anhydrous MgSO4 and concentrated under reduced pressure to give a residue which was purified by column chromatography (PE: EA = 1: 1) to provide compound 66b (159 mg, 55%).

Etapa 2: Las siguientes etapas de-Boc y de acoplamiento final fueron similares a las del Ejemplo 48. El compuesto del titulo (61 mg, 71 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,89(s, 1H), 8,16-8,17(d, 1H), 7,62-7,78(m, 3H), 7,24-7,28(dd, 1H), 7,05-7,07(d, 1H), 6,81-6,95(m, 2H), 3,88-3,93(m, 1H), 3,65-3,69(d, 2H), 3,17-3,26(m, 2H), 2,79-2,88(m, 2H), 2,40-2,42(ds, 6H), 2,34(s, 3H), 1,84- 1,92(m, 2H), 1,56-1,67(m, 2H). CL/EM: 474,2 [M+H]+.Stage 2: The following de-Boc and final coupling steps were similar to those in Example 48. The title compound (61 mg, 71%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.89 (s, 1H), 8.16-8.17 (d, 1H), 7.62-7, 78 (m, 3H), 7.24-7.28 (dd, 1H), 7.05-7.07 (d, 1H), 6.81-6.95 (m, 2H), 3.88- 3.93 (m, 1H), 3.65-3.69 (d, 2H), 3.17-3.26 (m, 2H), 2.79-2.88 (m, 2H), 2, 40-2.42 (ds, 6H), 2.34 (s, 3H), 1.84-192 (m, 2H), 1.56-1.67 (m, 2H). LC / MS: 474.2 [M + H] +.

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El compuesto del titulo (64 mg, 65 %) se sintetizo en forma de un solido de color naranja siguiendo el procedimiento del Ejemplo 67. RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,89(s, 1H), 7,92-7,95(d, 1H), 7,71-7,82(m, 3H), 7,00-7,03(d, 1H), 6,81-6,95(m, 3H), 4,54-4,58(m, 1H), 3,54-3,59(m, 1H), 3,37-3,42(m, 1h), 3,28-3,30(m, 3H), 3,15- 3,20(c, 1H), 2,38-2,40(ds, 6H), 2,29(s, 3H), 2,22-2,27(m, 1H), 1,99-2,05(m, 1H). CL/EM: 460,2 [M+H]+.The title compound (64 mg, 65%) was synthesized in the form of an orange solid following the procedure of Example 67. 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.89 (s, 1H), 7.92-7.95 (d, 1H), 7.71-7.82 (m, 3H), 7.00-7.03 (d, 1H), 6, 81-6.95 (m, 3H), 4.54-4.58 (m, 1H), 3.54-3.59 (m, 1H), 3.37-3.42 (m, 1h), 3.28-3.30 (m, 3H), 3.15-3.20 (c, 1H), 2.38-2.40 (ds, 6H), 2.29 (s, 3H), 2, 22-2.27 (m, 1H), 1.99-2.05 (m, 1H). LC / MS: 460.2 [M + H] +.

Ejemplo 69: Preparacion de [(S)-2-oxo-1-(tetrahidro-piran-4-ilmetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro- 2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetiMH-pirrol-3-carboxilicoExample 69: Preparation of [(S) -2-oxo-1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2 -dihydro-mdol- (3Z) -ylidenmethyl] -2,4-dimetiMH-pyrrole-3-carboxylic

imagen91image91

El compuesto del titulo (30 mg, 50 %) se sintetizo en forma de un solido de color naranja siguiendo el procedimiento del Ejemplo 60. RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,91(s, 1H), 7,71-7,88(m, 3H), 6,82-6,96(m, 2H), 4,60-4,62(c, 1H), 3,82-3,85(d, 2H), 2,29-3,31(m, 6H), 2,42-2,44(ds, 6H), 2,31-2,35(m, 1H), 1,84-1,98(m, 2H), 1,49- 1,58(m, 2H), 1,05-1,19(m, 2H). CL/EM: 481,0 [M+H]+.The title compound (30 mg, 50%) was synthesized in the form of an orange solid following the procedure of Example 60. 1H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1H), 10.91 (s, 1H), 7.71-7.88 (m, 3H), 6.82-6.96 (m, 2H), 4.60-4.62 (c, 1H), 3, 82-3.85 (d, 2H), 2.29-3.31 (m, 6H), 2.42-2.44 (ds, 6H), 2.31-2.35 (m, 1H), 1.84-1.98 (m, 2H), 1.49-1.58 (m, 2H), 1.05-1.19 (m, 2H). LC / MS: 481.0 [M + H] +.

Ejemplo 70: Preparacion de [1-(2-metanosulfonil-etil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetiMH-pirrol-3-carboxilicoExample 70: Preparation of [1- (2-methanesulfonyl-ethyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl ] -2,4-dimetiMH-pyrrole-3-carboxylic

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Etapa 1: Se anadio una solucion acuosa al 30 % de H2O2 (5 ml) a una solucion de 70a (900 mg, 8,2 mmol) en acido acetico (5 ml) a temperatura ambiente. Durante la adicion, se desprendio calor. La mezcla resultante se agito durante una noche a temperatura ambiente y se evaporo. El residuo se purifico por cromatografia en columna (AE:PE = 1:4) para proporcionar 70b (538 mg, 46 %) en forma de un aceite incoloro.Step 1: A 30% aqueous solution of H2O2 (5 ml) was added to a solution of 70a (900 mg, 8.2 mmol) in acetic acid (5 ml) at room temperature. During the addition, heat was released. The resulting mixture was stirred overnight at room temperature and evaporated. The residue was purified by column chromatography (EA: PE = 1: 4) to provide 70b (538 mg, 46%) as a colorless oil.

Las etapas posteriores son similares a las del Ejemplo 62. El compuesto del titulo (97 mg, 84 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,66(s, 1H), 10,90(s, 1H), 7,55-7,79(m, 3H), 6,81- 6,96(m, 2H), 3,71-3,74(m, 1H), 3,26-3,31 (m, 2H), 3,04(s, 3H), 2,85-2,89(m, 2H), 2,68-2,72(t, 2H), 2,39-2,41 (ds, 6H),The subsequent steps are similar to those of Example 62. The title compound (97 mg, 84%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.66 (s, 1H), 10.90 (s, 1H), 7.55-7.79 (m, 3H), 6.81-6, 96 (m, 2H), 3.71-3.74 (m, 1H), 3.26-3.31 (m, 2H), 3.04 (s, 3H), 2.85-2.89 ( m, 2H), 2.68-2.72 (t, 2H), 2.39-2.41 (ds, 6H),

2,04-2,12(t, 2H), 1,76-1,82(m, 2H), 1,49-1,56(m, 2h). CL/EM: 487,2 [M-H]+.2.04-2.12 (t, 2H), 1.76-1.82 (m, 2H), 1.49-1.56 (m, 2h). LC / MS: 487.2 [M-H] +.

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Ejemplo 71: Preparacion de [(S)-1-(2-metanosulfonil-etil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 71: Preparation of [(S) -1- (2-methanesulfonyl-ethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- ( 3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

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El compuesto del tftulo (96 mg, 84 %) se sintetizo en forma de un solido de color naranja siguiendo el procedimiento del Ejemplo 70. RMN 1H (300 MHz, DMSO-d6): 5 = 13,67(s, 1H), 10,90(s, 1H), 7,71-7,80(m, 3H), 6,81-6,96(m, 2H), 4,35-4,37(m, 1H), 3,27-3,34(m, 4H), 3,04(s, 3H), 2,68-2,81(m, 4H), 2,39-2,41(ds, 6H), 2,11-2,18(m, 1H), 1,68-1,74(m, 1H). CL/EM: 473,2 [M-H]+.The title compound (96 mg, 84%) was synthesized in the form of an orange solid following the procedure of Example 70. 1 H NMR (300 MHz, DMSO-d6): 5 = 13.67 (s, 1 H), 10.90 (s, 1H), 7.71-7.80 (m, 3H), 6.81-6.96 (m, 2H), 4.35-4.37 (m, 1H), 3, 27-3.34 (m, 4H), 3.04 (s, 3H), 2.68-2.81 (m, 4H), 2.39-2.41 (ds, 6H), 2.11- 2.18 (m, 1H), 1.68-1.74 (m, 1H). LC / MS: 473.2 [M-H] +.

Ejemplo 72: Preparacion de [(R)-2-(2-metanosulfonil-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro- 2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 72: Preparation of [(R) -2- (2-methanesulfonyl-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro -indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

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Etapa 1: El compuesto 44a (100 mg, 0,5 mmol), 70b (86 mg, 0,61 mmol), KI (86 mg, 0,52 mmol), K2CO3 (342 mg, 2,48 mmol) y acetonitrilo (20 ml) se mezclaron en un vial para microondas. La mezcla resultante se hizo reaccionar en condiciones de microondas a 140 °C durante 1 h. Despues de enfriarse, la mezcla se filtro. El filtrado se evaporo y el residuo se purifico por cromatografia en columna (AE) para proporcionar 72a (82 mg, 49 %).Stage 1: Compound 44a (100 mg, 0.5 mmol), 70b (86 mg, 0.61 mmol), KI (86 mg, 0.52 mmol), K2CO3 (342 mg, 2.48 mmol) and acetonitrile (20 ml) were mixed in a microwave vial. The resulting mixture was reacted under microwave conditions at 140 ° C for 1 h. After cooling, the mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography (EA) to provide 72a (82 mg, 49%).

Las etapas posteriores son similares a las del Ejemplo 48. El compuesto del titulo (71 mg, 81 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,73(s, 1H), 10,93(s, 1H), 8,13-8,16(d, 1H), 7,73- 7,80(m, 2H), 6,82-6,97(m, 2H), 4,96-5,05(c, 1H), 4,59-4,64(t, 1H), 4,08-4,14(t, 1H), 3,91-3,96(t, 2H), 3,44-3,49(t, 2H), 3,06(s, 3H), 2,43-2,45(ds, 6H). CL/EM: 491,0 [M+H]+.The subsequent steps are similar to those of Example 48. The title compound (71 mg, 81%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.73 (s, 1H), 10.93 (s, 1H), 8.13-8.16 (d, 1H), 7.73-7, 80 (m, 2H), 6.82-6.97 (m, 2H), 4.96-5.05 (c, 1H), 4.59-4.64 (t, 1H), 4.08- 4.14 (t, 1H), 3.91-3.96 (t, 2H), 3.44-3.49 (t, 2H), 3.06 (s, 3H), 2.43-2, 45 (ds, 6H). LC / MS: 491.0 [M + H] +.

Ejemplo 73: Preparacion de [(S)-2-(2-metoxietil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 73: Preparation of [(S) -2- (2-methoxyethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole - (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

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Etapa 1: El compuesto 73a (500 mg, 4,9 mmol) y TEA (990 mg, 9,8 mmol) se disolvieron en una mezcla de THF/agua (75 ml, VN 2:1). Se anadio gota a gota (Boc)2O (1,18 g, 5,4 mmol) en refrigeracion con hielo. Despues deStep 1: Compound 73a (500 mg, 4.9 mmol) and TEA (990 mg, 9.8 mmol) were dissolved in a mixture of THF / water (75 ml, VN 2: 1). (Boc) 2O (1.18 g, 5.4 mmol) was added dropwise under ice cooling. After

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que se completase la adicion, la mezcla se calento a temperatura ambiente y se agito durante una noche. La mezcla se evaporo a sequedad y el residuo se purifico por cromatografia en columna (AE:PE = 1:3) para proporcionar el compuesto 73b (406 mg, 41 %) en forma de un solido de color blanco.When the addition was completed, the mixture was heated to room temperature and stirred overnight. The mixture was evaporated to dryness and the residue was purified by column chromatography (EA: PE = 1: 3) to give compound 73b (406 mg, 41%) as a white solid.

Etapa 2: El compuesto 73b (200 mg, 0,935 mmol), 1-bromo-2-metoxi-etano (156 mg, 1,12 mmol), KI (163 mg, 0,98 mmol), K2CO3 (645 mg, 4,68 mmol) y acetonitrilo (20 ml) se mezclaron en un vial para microondas. La mezcla resultante se hizo reaccionar en condiciones de microondas a 140 °C durante 1 h. Despues de enfriarse, la mezcla se filtro. El filtrado se evaporo y el residuo se purifico por cromatografia en columna (AE:PE = 1:3) para proporcionar 73c (138 mg, 54 %).Stage 2: Compound 73b (200 mg, 0.935 mmol), 1-bromo-2-methoxy-ethane (156 mg, 1.12 mmol), KI (163 mg, 0.98 mmol), K2CO3 (645 mg, 4 , 68 mmol) and acetonitrile (20 ml) were mixed in a microwave vial. The resulting mixture was reacted under microwave conditions at 140 ° C for 1 h. After cooling, the mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography (EA: PE = 1: 3) to provide 73c (138 mg, 54%).

Etapa 3: Las siguientes etapas de de-Boc y de acoplamiento final fueron similares a los del Ejemplo 48. El compuesto del titulo (83 mg, 83 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,94(s, 1H), 8,12-8,15(d, 1H), 7,73-7,80(m, 2H), 6,82-6,97(m, 2H), 5,00-5,06(c, 1H), 4,57-4,63(t, 1H), 4,01-4,07(m, 1H), 3,45-3,71(m, 4H), 3,27(s, 3H), 2,43-2,45(ds, 6H). CL/EM: 442,9 [M+H]+.Step 3: The following stages of de-Boc and final coupling were similar to those of Example 48. The title compound (83 mg, 83%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.94 (s, 1H), 8.12-8.15 (d, 1H), 7.73-7, 80 (m, 2H), 6.82-6.97 (m, 2H), 5.00-5.06 (c, 1H), 4.57-4.63 (t, 1H), 4.01- 4.07 (m, 1H), 3.45-3.71 (m, 4H), 3.27 (s, 3H), 2.43-2.45 (ds, 6H). LC / MS: 442.9 [M + H] +.

Ejemplo 74: Preparacion de [(R)-2-(2-etoxietil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxflicoExample 74: Preparation of [(R) -2- (2-ethoxyethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole - (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic

imagen96image96

Siguiendo el procedimiento del Ejemplo 44, el compuesto del titulo (42 mg, 91 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,73(s, 1H), 10,94(s, 1H), 8,11-8,14(d, 1H), 7,73-7,80(m, 2H),Following the procedure of Example 44, the title compound (42 mg, 91%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.73 (s, 1H), 10.94 (s, 1H), 8.11-8.14 (d, 1H), 7.73-7, 80 (m, 2H),

6,82-6,97(m, 2H), 5,02-5,05(c, 1H), 4,37-4,63(t, 1H), 4,01-4,07(m, 1H), 3,40-3,70(m, 6H), 2,43-2,45(ds, 6H), 1,03- 1,17(m, 3H). CL/EM: 457,2 [M+H]+.6.82-6.97 (m, 2H), 5.02-5.05 (c, 1H), 4.37-4.63 (t, 1H), 4.01-4.07 (m, 1H ), 3.40-3.70 (m, 6H), 2.43-2.45 (ds, 6H), 1.03-1.17 (m, 3H). LC / MS: 457.2 [M + H] +.

Ejemplo 75: Preparacion de [(S)-1-(2-metoxietil)-2,5-dioxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-Example 75: Preparation of [(S) -1- (2-methoxyethyl) -2,5-dioxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-

1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMico1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

imagen97image97

Etapa 1: A una solucion de 75a (2,0 g 15 mmol), Na2CO3 (1,6 g, 15 mmol) en H2O/1,4-dioxano (30 ml/30 ml) se le anadio gota a gota (Boc)2O (3,96 g, 18,2 mmol) a temperatura ambiente. La mezcla se agito durante una noche y se evaporo para retirar 1,4-dioxano. La solucion acuosa obtenida se ajusto a pH = 2 con HCl al 37 %. El precipitado formado se filtro, se lavo con agua y se seco para proporcionar 75b (2,97 g, 84 %) en forma de un solido de color blanco.Step 1: To a solution of 75a (2.0 g 15 mmol), Na2CO3 (1.6 g, 15 mmol) in H2O / 1,4-dioxane (30 ml / 30 ml) was added dropwise (Boc ) 2O (3.96 g, 18.2 mmol) at room temperature. The mixture was stirred overnight and evaporated to remove 1,4-dioxane. The aqueous solution obtained was adjusted to pH = 2 with 37% HCl. The precipitate formed was filtered, washed with water and dried to provide 75b (2.97 g, 84%) as a white solid.

Etapa 2: A una solucion agitada de 75b (2,0 g, 8,62 mmol) en DMF (15 ml) se le anadieron DCC (1,775 g, 8,62 mmol) y HOSu (0,99 g, 8,62 mmol). La mezcla se calento a 80 °C con agitacion durante 6 h. Se evaporo DMF y el residuo se disolvio en AE (25 ml) y se filtro. El filtrado se lavo con agua y salmuera y se seco por Na2SO4. Despues de la evaporation, el residuo se purifico por cromatografia en columna (AE:PE = 1:1) para proporcionar un solido de color amarillo palido que se recristalizo en AE para dar 75c (0,83 g, 45 %) en forma de un solido de color blanco.Step 2: To a stirred solution of 75b (2.0 g, 8.62 mmol) in DMF (15 ml) was added DCC (1,775 g, 8.62 mmol) and HOSu (0.99 g, 8.62 mmol). The mixture was heated at 80 ° C with stirring for 6 h. DMF was evaporated and the residue was dissolved in EA (25 ml) and filtered. The filtrate was washed with water and brine and dried over Na2SO4. After evaporation, the residue was purified by column chromatography (EA: PE = 1: 1) to provide a pale yellow solid that was recrystallized from EA to give 75c (0.83 g, 45%) as A solid white.

Etapa 3: Las etapas posteriores son similares a las del Ejemplo 73 para obtener el compuesto del titulo (83 mg, 90 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,73(s, 1H), 10,92(s, 1H), 8,17- 8,19(d, 1H), 7,72-7,79(m, 2H), 6,82-6,97(m, 2H), 4,63-4,71(m, 1H), 3,58-3,63(c, 2H), 3,43-3,47(t, 2H), 3,30(s, 3H), 3,00-3,09(c, 1H), 2,63-2,70(dd, 1H), 2,43-2,44(ds, 6H). CL/EM: 455,0 [M+H]+.Stage 3: The subsequent steps are similar to those in Example 73 to obtain the title compound (83 mg, 90%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.73 (s, 1H), 10.92 (s, 1H), 8.17-8.19 (d, 1H), 7.72-7, 79 (m, 2H), 6.82-6.97 (m, 2H), 4.63-4.71 (m, 1H), 3.58-3.63 (c, 2H), 3.43- 3.47 (t, 2H), 3.30 (s, 3H), 3.00-3.09 (c, 1H), 2.63-2.70 (dd, 1H), 2.43-2, 44 (ds, 6H). LC / MS: 455.0 [M + H] +.

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imagen98image98

Etapa 1: A una solucion de 76a (250 mg 2,45 mmol), TEA (273 mg, 2,7 mmol) en DCM (20 ml) se le anadio gota a gota cloruro de metano sulfonilo (298 mg, 2,6 mmol) a 0 °C. La mezcla se agito durante una noche a temperatura ambiente. Despues de que la reaccion se completase, la mezcla se lavo con una solucion de Na2CO3. La fase organica se separo y la fase acuosa se extrajo con DCM (20 ml x 3). La fase organica se combino, se seco sobre Na2SO4 anhidro y se evaporo para proporcionar 76b (387 mg, 88 %) en forma de un aceite.Step 1: To a solution of 76a (250 mg 2.45 mmol), TEA (273 mg, 2.7 mmol) in DCM (20 ml) methane sulfonyl chloride (298 mg, 2.6) was added dropwise mmol) at 0 ° C. The mixture was stirred overnight at room temperature. After the reaction was completed, the mixture was washed with a Na2CO3 solution. The organic phase was separated and the aqueous phase was extracted with DCM (20 ml x 3). The organic phase was combined, dried over anhydrous Na2SO4 and evaporated to provide 76b (387 mg, 88%) as an oil.

Las etapas posteriores son similares a las del Ejemplo 72 para obtener el compuesto del tftulo (33 mg, 78 %) obtenido en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,92(s, 1H), 8,13-8,16(d, 1H), 7,73-7,79(m, 2H), 6,82-6,97(m, 2H), 5,01-5,10(c, 1H), 4,58-4,63(t, 2H), 4,04-4,11(m, 1H), 3,40- 3,76(m, 6H), 2,72-2,88(m, 1H), 2,43-2,45(ds, 6H), 1,95-2,01 (m, 1H), 1,59-1,63(m, 1H). CL/EM: 469,2 [M+H]+.The subsequent steps are similar to those of Example 72 to obtain the title compound (33 mg, 78%) obtained in the form of an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.92 (s, 1H), 8.13-8.16 (d, 1H), 7.73-7, 79 (m, 2H), 6.82-6.97 (m, 2H), 5.01-5.10 (c, 1H), 4.58-4.63 (t, 2H), 4.04- 4.11 (m, 1H), 3.40-3.76 (m, 6H), 2.72-2.88 (m, 1H), 2.43-2.45 (ds, 6H), 1, 95-2.01 (m, 1H), 1.59-1.63 (m, 1H). LC / MS: 469.2 [M + H] +.

Ejemplo 77: Preparacion de [(R)-3-oxo-2-(tetrahidro-furan-2-ilmetil)-isoxazolidin-4-il]-amida del acido 5-[5- fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxMicoExample 77: Preparation of [(R) -3-oxo-2- (tetrahydro-furan-2-ylmethyl) -isoxazolidin-4-yl] -amide of the acid 5- [5- fluoro-2-oxo-1,2 -dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxMico

imagen99image99

Siguiendo el procedimiento del Ejemplo 76, el compuesto del tftulo (20 mg, 72 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,92(s, 1H), 8,10-8,14(m, 1H), 7,73-7,79(m, 2H),Following the procedure of Example 76, the title compound (20 mg, 72%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.92 (s, 1H), 8.10-8.14 (m, 1H), 7.73-7, 79 (m, 2H),

6,82-6,94(m, 2H), 5,00-5,10(m, 1H), 4,57-4,62(t, 1H), 4,02-4,08(m, 2H), 3,57-3,77(m, 3H), 2,42-2,48(m, 1H), 2,40- 2,49(ds, 6H), 1,60-1,93(m, 4H). CL/EM: 468,9 [M+H]+.6.82-6.94 (m, 2H), 5.00-5.10 (m, 1H), 4.57-4.62 (t, 1H), 4.02-4.08 (m, 2H ), 3.57-3.77 (m, 3H), 2.42-2.48 (m, 1H), 2.40-2.49 (ds, 6H), 1.60-1.93 (m , 4H). LC / MS: 468.9 [M + H] +.

Ejemplo 78: Preparacion de [(S)-2,5-dioxo-1-(tetrahidro-piran-4-ilmetil)-pirrolidin-3-il]-amida del acido 5-[5- fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxflicoExample 78: Preparation of [(S) -2,5-dioxo-1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5- fluoro-2-oxo-1 , 2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxylic acid

imagen100image100

75c75c

60a60th

78a78th

Etapa 1: El compuesto 75c (200 mg, 0,93 mmol), 60a (201 mg, 1,12 mmol), KI (163 mg, 0,98 mmol), K2CO3 (644 mg, 4,67 mmol) y acetonitrilo (20 ml) se mezclaron en un vial para microondas. La mezcla resultante se hizo reaccionar en condiciones de microondas a 140 °C durante 1 h. Despues de enfriarse, la mezcla se filtro. El filtrado se evaporo y el residuo se purifico por cromatograffa en columna (AE:PE = 1:3) para proporcionar 78a (224 mg, 77 %).Stage 1: Compound 75c (200 mg, 0.93 mmol), 60a (201 mg, 1.12 mmol), KI (163 mg, 0.98 mmol), K2CO3 (644 mg, 4.67 mmol) and acetonitrile (20 ml) were mixed in a microwave vial. The resulting mixture was reacted under microwave conditions at 140 ° C for 1 h. After cooling, the mixture was filtered. The filtrate was evaporated and the residue was purified by column chromatography (EA: PE = 1: 3) to provide 78a (224 mg, 77%).

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45Four. Five

Las etapas posteriores son similares a las del Ejemplo 48 para obtener el compuesto del titulo (60 mg, 72 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,72(s, 1H), 10,93(s, 1H), 8,22-8,24(d, 1H), 7,72-7,79(m, 2H), 6,82-6,97(m, 2H), 4,58-4,65(m, 1H), 3,81-3,85(m, 1H), 3,20-3,32(m, 4H), 2,97-3,06(c, 1H), 2,65- 2,72(dd, 1H), 2,42-2,43(ds, 6H), 1,84-1,89(m, 1H), 1,58-1,64(m, 2H), 1,15-1,23(m, 2H). CL/EM: 495,2 [M+H]+.The subsequent steps are similar to those in Example 48 to obtain the title compound (60 mg, 72%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.72 (s, 1H), 10.93 (s, 1H), 8.22-8.24 (d, 1H), 7.72-7, 79 (m, 2H), 6.82-6.97 (m, 2H), 4.58-4.65 (m, 1H), 3.81-3.85 (m, 1H), 3.20- 3.32 (m, 4H), 2.97-3.06 (c, 1H), 2.65-2.72 (dd, 1H), 2.42-2.43 (ds, 6H), 1, 84-1.89 (m, 1H), 1.58-1.64 (m, 2H), 1.15-1.23 (m, 2H). LC / MS: 495.2 [M + H] +.

Ejemplo 79: Preparacion de [(S)-2,5-dioxo-1-(tetrahidro-piran-4-il)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2- oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNicoExample 79: Preparation of [(S) -2,5-dioxo-1- (tetrahydro-pyran-4-yl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2- oxo-1 , 2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxy

imagen101image101

Siguiendo el procedimiento del Ejemplo 48, el compuesto del titulo (71 mg, 62 %) se obtuvo en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,73(s, 1H), 10,92(s, 1H), 8,17-8,20(d, 1H), 7,73-7,79(m, 2H),Following the procedure of Example 48, the title compound (71 mg, 62%) was obtained as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.73 (s, 1H), 10.92 (s, 1H), 8.17-8.20 (d, 1H), 7.73-7, 79 (m, 2H),

6,82-6,97(m, 2H), 4,55-4,62(m, 1H), 4,10-4,18(m, 1H), 3,90-3,95(dd, 2H), 3,32-3,39(m, 2H), 2,93-3,02(c, 1H), 2,59- 2,67(dd, 1H), 2,38-2,43(ds, 6H), 2,26-2,37(m, 2H), 1,48-1,51 (d, 2H). CL/EM: 481,2 [M+H]+.6.82-6.97 (m, 2H), 4.55-4.62 (m, 1H), 4.10-4.18 (m, 1H), 3.90-3.95 (dd, 2H ), 3.32-3.39 (m, 2H), 2.93-3.02 (c, 1H), 2.59-2.67 (dd, 1H), 2.38-2.43 (ds , 6H), 2.26-2.37 (m, 2H), 1.48-1.51 (d, 2H). LC / MS: 481.2 [M + H] +.

Ejemplo 80: Preparacion de ((S)-1-dimetilcarbamoil-2-oxo-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-Example 80: Preparation of ((S) -1-dimethylcarbamoyl-2-oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-

1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxy

imagen102image102

A una solucion de 40a (200 mg, 1,0 mmol) en DMF (10 ml) se le anadio NaH al 60 % (80 mg, 2,0 mmol) a 0 °C. Despues de agitar durante 1 h mas a temperatura ambiente, a la mezcla se le anadio el compuesto 80a (118 mg, 1,1 mmol). La mezcla resultante se agito a temperatura ambiente durante una noche y se evaporo. El residuo se purifico por cromatografia en columna (AE:PE = 1:1) para proporcionar 80b (98 mg, 36 %).To a solution of 40a (200 mg, 1.0 mmol) in DMF (10 ml), 60% NaH (80 mg, 2.0 mmol) was added at 0 ° C. After stirring for an additional 1 h at room temperature, compound 80a (118 mg, 1.1 mmol) was added to the mixture. The resulting mixture was stirred at room temperature overnight and evaporated. The residue was purified by column chromatography (EA: PE = 1: 1) to provide 80b (98 mg, 36%).

Las etapas posteriores son similares a las del Ejemplo 48 para obtener el compuesto del titulo (83 mg, 76 %) en forma de un solido de color naranja. RMN 1H (300 MHz, DMSO-d6): 5 = 13,70(s, 1H), 10,90(s, 1H), 8,04-8,07(m, 1H), 7,72-7,78(m, 2H), 6,82-6,96(m, 2H), 4,36-4,53(m, 1H), 3,57-3,62(m, 2H), 2,92(s,6H), 2,42-2,45(ds, 6H), 2,30- 2,34(m,2H),2,12-2,19(m, 2H). CL/EM: 453,8 [M+H]+.The subsequent steps are similar to those in Example 48 to obtain the title compound (83 mg, 76%) as an orange solid. 1H NMR (300 MHz, DMSO-d6): 5 = 13.70 (s, 1H), 10.90 (s, 1H), 8.04-8.07 (m, 1H), 7.72-7, 78 (m, 2H), 6.82-6.96 (m, 2H), 4.36-4.53 (m, 1H), 3.57-3.62 (m, 2H), 2.92 ( s, 6H), 2.42-2.45 (ds, 6H), 2.30-2.34 (m, 2H), 2.12-2.19 (m, 2H). LC / MS: 453.8 [M + H] +.

Los compuestos de las tablas en el presente documento se preparan de una manera similar como se ha descrito anteriormente y en los esquemas generales.The compounds of the tables herein are prepared in a similar manner as described above and in the general schemes.

Ejemplo 81: Evaluacion de actividad biologicaExample 81: Evaluation of biological activity

Ensayo bioquimico de VEGFR2 (KDR)VEGFR2 biochemical assay (KDR)

Los compuestos se ensayan para la actividad bioquimica esencialmente de acuerdo con el siguiente procedimiento. En un volumen de reaccion final de 25 pl, se incuba KDR (h) (5-10 mU) con MOPS 8 mM pH 7,0, EdTA 0,2 mM, 0,33 mg/ml de proteina basica de mielina, MgAcetato 10 mM y [(y-33P-ATP)] (actividad especifica aproximada 500 cpm/pmol, concentracion segun la necesaria). La reaccion se inicia mediante la adicion de la mezcla MgATP. Despues de incubacion durante 40 minutos a temperatura ambiente, la reaccion se detiene mediante la adicion de 5 pl de una solucion de acido fosforico al 3 %. Despues se aplican puntualmente 10 pl de la reaccion sobre una malla de filtro P30 y se lavan tres veces durante 5 minutos en acido fosforico 75 mM y una vez en metanol antes del secado y el recuente de centelleo.The compounds are tested for biochemical activity essentially in accordance with the following procedure. In a final reaction volume of 25 pl, KDR (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EdTA, 0.33 mg / ml myelin basic protein, MgAcetate 10 mM and [(y-33P-ATP)] (specific activity approximately 500 cpm / pmol, concentration as necessary). The reaction is initiated by the addition of the MgATP mixture. After incubation for 40 minutes at room temperature, the reaction is stopped by adding 5 pl of a 3% phosphoric acid solution. Then 10 pl of the reaction are applied promptly on a P30 filter mesh and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and scintillation counting.

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Ensayo bioquimico de PDGFRpPDGFRp biochemical assay

Los compuestos se ensayan para la actividad bioqmmica esencialmente de acuerdo con el siguiente procedimiento. En un volumen de reaccion final de 25 pl, se incuba PDGFRp (h) (5-10 mU) con MOPS 8 mM pH 7,0, EDTA 0,2 mM, 0,1 mg/ml de poli(Glu, Tyr) 4:1, MgCl2 10 mM, MgAcetato 10 mM y [(Y-33P-ATP)] (actividad especifica aproximada 500 cpm/pmol, concentration segun la necesaria). La reaccion se inicia mediante la adicion de la mezcla MgATP. Despues de incubation durante 40 minutos a temperatura ambiente, la reaccion se detiene mediante la adicion de 5 pl de una solution de acido fosforico al 3 %. Despues se aplican puntualmente 10 pl de la reaccion sobre una malla de filtro A y se lavan tres veces durante 5 minutos en acido fosforico 75 mM y una vez en metanol antes del secado y el recuente de centelleo.The compounds are tested for biochemical activity essentially in accordance with the following procedure. In a final reaction volume of 25 pl, PDGFRp (h) (5-10 mU) is incubated with 8 mM MOPS pH 7.0, 0.2 mM EDTA, 0.1 mg / ml poly (Glu, Tyr) 4: 1, 10 mM MgCl2, 10 mM MgAcetate and [(Y-33P-ATP)] (specific activity approximately 500 cpm / pmol, concentration as necessary). The reaction is initiated by the addition of the MgATP mixture. After incubation for 40 minutes at room temperature, the reaction is stopped by adding 5 pl of a 3% phosphoric acid solution. Then 10 pl of the reaction are applied promptly on a filter mesh A and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and scintillation counting.

Ensayo bioqmmico de AMPKAMPK biochemical test

Los compuestos se ensayan para la actividad bioquimica esencialmente de acuerdo con el siguiente procedimiento. En un volumen de reaccion final de 25 pl, se incuba AMPK (r) (5-10 mU) con HEPES 32 mM pH 7,4, DTT 0,65 mM, Brij-35 al 0,012 %, AMP 200 pM, AMARAASAAALARRR 200 pM, MgAcetato 10 mM y [(Y-33P-ATP)] (actividad especifica aproximada 500 cpm/pmol, concentracion segun la necesaria). La reaccion se inicia mediante la adicion de la mezcla MgATP. Despues de incubacion durante 40 minutos a temperatura ambiente, la reaccion se detiene mediante la adicion de 5 pl de una solucion de acido fosforico al 3 %. Despues se aplican puntualmente 10 pl de la reaccion sobre una malla de filtroP30A y se lavan tres veces durante 5 minutos en acido fosforico 75 mM y una vez en metanol antes del secado y el recuente de centelleo.The compounds are tested for biochemical activity essentially in accordance with the following procedure. In a final reaction volume of 25 pl, AMPK (r) (5-10 mU) is incubated with 32 mM HEPES pH 7.4, 0.65 mM DTT, 0.012% Brij-35, AMP 200 pM, AMARAASAAALARRR 200 pM, 10 mM MgAcetate and [(Y-33P-ATP)] (specific activity approximately 500 cpm / pmol, concentration as necessary). The reaction is initiated by the addition of the MgATP mixture. After incubation for 40 minutes at room temperature, the reaction is stopped by adding 5 pl of a 3% phosphoric acid solution. Then 10 pl of the reaction are applied promptly on a P30A filter mesh and washed three times for 5 minutes in 75 mM phosphoric acid and once in methanol before drying and scintillation counting.

Algunos compuestos mostraron actividades inhibidoras de AMPK significativamente menores que Sunitinib. Incluyen, aunque sin limitation, los Ejemplos 17, 22, 25, 29, 30, 31, 36, y 48.Some compounds showed significantly lower AMPK inhibitory activities than Sunitinib. They include, but are not limited to, Examples 17, 22, 25, 29, 30, 31, 36, and 48.

Debe entenderse que aunque la invention se ha descrito con la description detallada de la misma, se pretende que la descripcion anterior ilustre y no limite el alcance de la invencion, que se define por el alcance de las reivindicaciones adjuntas. Otros aspectos, ventajas, y modificaciones estan dentro del alcance de las siguientes reivindicaciones.It should be understood that although the invention has been described with the detailed description thereof, it is intended that the foregoing description illustrates and does not limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims (27)

55 1010 15fifteen 20twenty 2525 3030 3535 4040 45Four. Five 50fifty 5555 REIVINDICACIONES 1. Un compuesto de formula (IN), o sal, solvato o hidrato farmaceuticos del mismo:1. A compound of formula (IN), or pharmaceutical salt, solvate or hydrate thereof: imagen1image 1 en la que Cy es una estructura dclica que puede ser cicloalquilo o heterodclico no aromatico, cada uno opcionalmente sustituido con Zi, Z2 y Z3;wherein Cy is a cyclic structure that can be non-aromatic cycloalkyl or heterodyl, each optionally substituted with Zi, Z2 and Z3; Ri es H;Ri is H; R2 es H;R2 is H; R3 es fluor;R3 is fluorine; cada uno de Zi, Z2 y Z3 es independientemente:Each of Zi, Z2 and Z3 is independently: (1) hidrogeno o Z6, donde Z6 es (i) alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo; (ii) un grupo (i) que esta a si mismo sustituido con uno o mas del mismo o diferentes grupos (i); o (iii) un grupo (i) o (ii) que esta sustituido con uno o mas de los siguientes grupos (2) a (13);(1) hydrogen or Z6, where Z6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl; (ii) a group (i) that is itself substituted with one or more of the same or different groups (i); or (iii) a group (i) or (ii) that is substituted with one or more of the following groups (2) to (13); (2) -OR o -OZi6;(2) -OR or -OZi6; (3) -SH o -SZi6;(3) -SH or -SZi6; (4) -C(O)2H, C(O)qZi6, -C(O)NZi7Zi8, -C(O)C(O)NZi7Zi8 o -O-C(O)qZi6, donde q es 1 o 2;(4) -C (O) 2H, C (O) qZi6, -C (O) NZi7Zi8, -C (O) C (O) NZi7Zi8 or -O-C (O) qZi6, where q is 1 or 2; (5) -SO3H, -S(O)qZi6 o -S(O)qNZi7Zi8;(5) -SO3H, -S (O) qZi6 or -S (O) qNZi7Zi8; (6) halo;(6) halo; (7) ciano;(7) cyano; (8) nitro;(8) nitro; (9) -Z4-NZ17Z18;(9) -Z4-NZ17Z18; (10) -Z4-N(Zi8)-Z5-NZi9Z20;(10) -Z4-N (Zi8) -Z5-NZi9Z20; (11) oxo;(11) oxo; (12) -O-C(O)-Zi6;(12) -O-C (O) -Zi6; (13) dos de Zi, Z2 y Z3 cualesquiera pueden ser juntos alquileno, alquenileno, arilo, heteroarilo o heterociclo completando un anillo saturado o insaturado de 3 a 8 miembros junto con los atomos a los que estan unidos;(13) two of any Zi, Z2 and Z3 may together be alkylene, alkenylene, aryl, heteroaryl or heterocycle by completing a saturated or unsaturated ring of 3 to 8 members together with the atoms to which they are attached; cada uno de Z4 y Z5 es independientementeeach of Z4 and Z5 is independently (1) un enlace sencillo;(1) a simple link; (2) -Zii-S(O)q-Zi2-;(2) -Zii-S (O) q-Zi2-; (3) -Zii-C(O)-Zi2-;(3) -Zii-C (O) -Zi2-; (4) -Z11-O-Z12-;(4) -Z11-O-Z12-; (5) -Z11-S-Z12-;(5) -Z11-S-Z12-; (6) -Zii-O-C(O)-Zi2-; o(6) -Zii-O-C (O) -Zi2-; or (7) -Zii-C(O)-O-Zi2;(7) -Zii-C (O) -O-Zi2; cada uno de Zii y Z12 es independientementeeach of Zii and Z12 is independently (1) un enlace sencillo;(1) a simple link; (2) alquileno;(2) alkylene; (3) alquenileno; o(3) alkenylene; or (4) alquinileno;(4) alkynylene; cada Zi6 es independientemente alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo, heterociclo o heterocicloalquilo, cada uno opcionalmente sustituido con uno o mas de los siguientes grupos:Each Zi6 is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocycle or heterocycloalkyl, each optionally substituted with one or more of the following groups: (2) -OH o -OZ21;(2) -OH or -OZ21; (3) -SH o -SZ21;(3) -SH or -SZ21; (4) -C(O)2H, C(O)qZ2i, -C(O)NZi7Zi8, -C(O)C(O)NZi7Zi8 o -O-C(O)qZ2i, donde q es 1 o 2;(4) -C (O) 2H, C (O) qZ2i, -C (O) NZi7Zi8, -C (O) C (O) NZi7Zi8 or -O-C (O) qZ2i, where q is 1 or 2; (5) -SO3H, -S(O)qZ2i o -S(O)qNZi7Zi8;(5) -SO3H, -S (O) qZ2i or -S (O) qNZi7Zi8; (6) halo;(6) halo; (7) ciano;(7) cyano; 55 1010 15fifteen 20twenty 2525 3030 3535 4040 45Four. Five 50fifty 5555 6060 6565 (8) nitro;(8) nitro; (9) -Z4-NZ17Z18;(9) -Z4-NZ17Z18; (10) -Z4-N(Zi8)-Z5-NZi9Z20;(10) -Z4-N (Zi8) -Z5-NZi9Z20; (11) oxo;(11) oxo; (12) -O-C(O)-Z2i;(12) -O-C (O) -Z2i; cada Z17 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Z17 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterociclo o heterocicloalquilo;heterocycle or heterocycloalkyl; cada Zi8 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Zi8 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterociclo o heterocicloalquilo;heterocycle or heterocycloalkyl; cada Z19 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Z19 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterociclo o heterocicloalquilo;heterocycle or heterocycloalkyl; cada Z20 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Z20 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterociclo o heterocicloalquilo;heterocycle or heterocycloalkyl; cada Z21 es independientemente hidrogeno, alquilo, alquenilo, alquinilo, cicloalquilo, cicloalquilalquilo,Each Z21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cicloalquenilo, cicloalquenilalquilo, arilo, heteroarilo, aralquilo, heteroarilalquilo, alquilarilo, cicloalquilarilo,cycloalkenyl, cycloalkenyl alkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterociclo o heterocicloalquilo; cada Z22 es independientemente,heterocycle or heterocycloalkyl; Each Z22 is independently, (2) -OH o -OZ21;(2) -OH or -OZ21; (3) -SH o -SZ21;(3) -SH or -SZ21; (4) -C(O)2H, C(O)qZ21, -C(O)NZ21Z21, -C(O)C(O)NZ21Z21 o -O-C(O)qZ21, donde q es 1 o 2;(4) -C (O) 2H, C (O) qZ21, -C (O) NZ21Z21, -C (O) C (O) NZ21Z21 or -O-C (O) qZ21, where q is 1 or 2; (5) -SO3H, -S(O)qZ21 o -S(O)qNZ21Z21;(5) -SO3H, -S (O) qZ21 or -S (O) qNZ21Z21; (6) halo;(6) halo; (7) ciano;(7) cyano; (8) nitro;(8) nitro; (9) -Z4-NZ21Z21;(9) -Z4-NZ21Z21; (10) -Z4-NZ2O-Z5-NZ21Z21;(10) -Z4-NZ2O-Z5-NZ21Z21; (11) oxo;(11) oxo; (12) -O-C(O)-Z21;(12) -O-C (O) -Z21; donde Z17 y Z18, o Z19 y Z20, junto con el atomo de nitrogeno al que estan unidos pueden ser un heterociclo que esta sin sustituir o sustituido con 1,2 o 3 Z22 independientes; ywhere Z17 and Z18, or Z19 and Z20, together with the nitrogen atom to which they are attached can be a heterocycle that is unsubstituted or substituted with independent 1,2 or 3 Z22; Y donde dos de Z18, Z19 o Z20 cualesquiera, junto con los atomos de nitrogeno a los que estan unidos pueden ser un anillo saturado o insaturado mono, bi o tri-heterociclico de 3 a 12 miembros que esta sin sustituir o sustituido con 1, 2 o 3 Z22 independientes.where two of any Z18, Z19 or Z20, together with the nitrogen atoms to which they are attached, can be a mono, bi or tri-heterocyclic saturated or unsaturated ring of 3 to 12 members that is unsubstituted or substituted with 1, 2 or 3 independent Z22. 2. El compuesto de la reivindicacion 1, en el que Cy es una estructura heterociclica no aromatica que esta opcionalmente sustituida con Z1, Z2 y Z3.2. The compound of claim 1, wherein Cy is a non-aromatic heterocyclic structure that is optionally substituted with Z1, Z2 and Z3. 3. El compuesto de la reivindicacion 1, en el que Cy es un anillo opcionalmente sustituido de 5 miembros no aromatico y heterociclico.3. The compound of claim 1, wherein Cy is an optionally substituted 5-membered non-aromatic and heterocyclic ring. 4. El compuesto de la reivindicacion 1, en el que Cy es un anillo opcionalmente sustituido de 6 miembros no aromatico heterociclico.4. The compound of claim 1, wherein Cy is an optionally substituted 6-membered non-aromatic heterocyclic ring. 5. El compuesto de la reivindicacion 1 que se selecciona entre:5. The compound of claim 1 selected from: (1-acetil-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-[3Z]-ilidenmetil]-2,4-dimetil-1H-pirrol-3- carboxilico,(1-Acetyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- [3Z] -ylidenmethyl] -2,4-dimethyl-1H-pyrrole -3- carboxylic, (1-metanosulfonil-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxilico,(1-Methanesulfonyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl- 1 H- pyrrole-3-carboxylic acid, N-(2H-3,4,5,6-tetrahidropiran-4-il){5-[(5-fluoro-2-oxo(1H-benzo[d]azolin-3-ilideno))metil]-2,4-dimetilpirrol-3-N- (2H-3,4,5,6-tetrahydropyran-4-yl) {5 - [(5-fluoro-2-oxo (1H-benzo [d] azolin-3-ylidene)) methyl] -2, 4-dimethylpyrrol-3- il}carboxamida,il} carboxamide, piperidin-4-ilamida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-d imetil-1 H-pirrol-3-carboxilico, ((S)-1-acetil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H- pirrol-3-carboxilico,piperidin-4-ylamide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-d -ethyl-1 H-pyrrole-3-carboxylic acid, ( (S) -1-Acetyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1H-pyrrole-3-carboxylic acid, ((S)-1-metanosulfonil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxilico,((S) -1-methanesulfonyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1 H-pyrrole-3-carboxylic acid, (1,1-dioxo-tetrahidro-tiofen-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,1,1-Dioxo-tetrahydro-thiophene-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl - 1 H-pyrrol-3-carboxNico, (1-pirimidin-2-il-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H- pirrol-3-carbox^lico,5- [5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl (1-pyrimidin-2-yl-piperidin-4-yl) -amide -1 H- pyrrole-3-carboxylic acid, (3,4,5,6-tetrahidro-2H-[1,3']bipiridinil-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,(3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxyNico, 55 1010 15fifteen 20twenty 2525 3030 3535 4040 45Four. Five 50fifty 5555 6060 6565 (4-hidroxi-1,1-dioxo-tetrahidro-tiofen-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,5- (5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2 (4-hydroxy-1,1-dioxo-tetrahydro-thiophene-3-yl) -amide , 4- dimethyl-1 H-pyrrole-3-carboxynic, (1,1-dioxohexahidro-tiopiran-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,(1,1-Dioxohexahydro-thiopiran-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H-Pyrrole-3-CarboxNico, ((S)-6-oxo-piperidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol- 3-carboxNico,((S) -6-Oxo-piperidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1 H-Pyrrole-3-CarboxNico, ((2S,3S,4R,5S,6S)-3,4,5-trihidroxi-6-hidroximetil-tetrahidro-piran-2-il)-amida del acido 5-[5-fluoro-2-oxo-1,2- dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,((2S, 3S, 4R, 5S, 6S) -3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl) -amide of the acid 5- [5-fluoro-2-oxo-1, 2- dihydro-mdol- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic, [1-(2-hidroxi-acetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[1- (2-Hydroxy-acetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2.4 -dimethyl- 1 H -pyrrole-3-carboxyNico, [(S)-1-(2-hidroxi-acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(S) -1- (2-Hydroxy-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4- dimethyl-1 H-pyrrole-3-carboxyNico, (4-hidroxi-tetrahidro-furan-3-il)-amida del acido 5-[5-1-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,5- (5-1-Fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidemethyl] -2,4-dimethyl acid (4-hydroxy-tetrahydro-furan-3-yl) -amide - 1 H-pyrrol-3-carboxNico, ((S)-2-oxo-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol- 3-carboxNico,((S) -2-Oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1 H-Pyrrole-3-CarboxNico, (1-bencil-4-hidroxi-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxiiico,5- [5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidemethyl] -2,4-dimethyl acid (1-benzyl-4-hydroxy-pyrrolidin-3-yl) -amide - 1 H-pyrrole-3-carboxylic acid, (1 -acetil-4-hidroxi-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,5- [5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidemethyl] -2,4-dimethyl (1-acetyl-4-hydroxy-pyrrolidin-3-yl) -amide - 1 H-pyrrol-3-carboxNico, (1-dimetilaminooxalil-piperidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,(1-Dimethylaminooxalyl-piperidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H- pyrrole-3-carboxynic, ((S)-1-dimetilaminooxalil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,((S) -1-Dimethylaminooxalyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2,4-dimethyl -1H-pyrrole-3-carboxNico, ((2S,3S,4R,5S)-3,4-dihidroxi-5-hidroximetil-tetrahidro-furan-2-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro- mdol-(3Z)-ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,((2S, 3S, 4R, 5S) -3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro- mdol- (3Z) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxyNico, ((S)-1-carbamoilmetil-2-oxo-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,((S) -1-carbamoylmethyl-2-oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2 , 4- dimethyl-1H-pyrrole-3-carboxynic, [(S)-1-(2-hidroxi-etil)-2-oxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,[(S) -1- (2-Hydroxy-ethyl) -2-oxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxyNico, [(R)-2-(2-hidroxi-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(R) -2- (2-Hydroxy-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ilidenmethyl] - 2.4- dimetil-1H-pirrol-3-carbox^lico,2.4-dimethyl-1H-pyrrole-3-carboxylic acid, ((R)-2-dimetilcarbamoilmetil-3-oxo-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,((R) -2-Dimethylcarbamoylmethyl-3-oxo-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2 , 4-dimethyl-1H-pyrrole-3-carboxyNico, ((R)-2-etil-3-oxo-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,((R) -2-Ethyl-3-oxo-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2 , 4-dimethyl-1 H-pyrrole-3-carboxynic, ((R)-2-carbamoilmetil-3-oxo-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-((R) -2-carbamoylmethyl-3-oxo-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2.4- dimetil-1H-pirrol-3-carbox^lico,2.4-dimethyl-1H-pyrrole-3-carboxylic acid, [(R)-2-(2-metoxi-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(R) -2- (2-Methoxy-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ilidenmethyl] - 2.4- dimetil-1H-pirrol-3-carbox^lico,2.4-dimethyl-1H-pyrrole-3-carboxylic acid, ((R)-3-oxo-2-piridin-3-ilmetil-isoxazolidin-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-((R) -3-Oxo-2-pyridin-3-ylmethyl-isoxazolidin-4-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmetil] - 2.4- dimetil-1H-pirrol-3-carbox^lico,2.4-dimethyl-1H-pyrrole-3-carboxylic acid, [(R)-3-oxo-2-(tetrahidro-piran-4-il)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-[(R) -3-Oxo-2- (tetrahydro-pyran-4-yl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico, [(R)-3-oxo-2-(tetrahidro-furan-3-il)-isoxazolidin-4-il]-amida del acido 5-[5-Fluoro-2-oxo-1,2-dihidro-indol-(3Z)-[(R) -3-Oxo-2- (tetrahydro-furan-3-yl) -isoxazolidin-4-yl] -amide of the acid 5- [5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico, [1-(morfolina-4-carbonil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,[1- (Morpholine-4-carbonyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2.4 - dimethyl-1H-pyrrole-3-carboxynic, [(S)-1-(morfolina-4-carbonil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,[(S) -1- (morpholine-4-carbonyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4- dimethyl-1H-pyrrole-3-carboxyNico, dimetilamida del acido 4-({5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3-carbonil}- amino)-piperidina-1-carbox^lico,Acid dimethylamide 4 - ({5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrol-3-carbonyl} -amino ) -piperidine-1-carboxylic acid, ((S)-1-dimetilcarbamoil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,((S) -1-Dimethylcarbamoyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl -1H-pyrrole-3-carboxNico, [1-(2-metoxi-acetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[1- (2-Methoxy-acetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2.4 -dimethyl- 1 H -pyrrole-3-carboxyNico, [(S)-1-(2-metoxi-acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,[(S) -1- (2-Methoxy-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4- dimethyl-1H-pyrrole-3-carboxyNico, N-((3R)oxolan-3-il){5-[(5-fluoro-2-oxo(1H-benzo[d]azolin-3-ilideno))metil]-2,4-dimetilpirrol-3-il}carboxamida, [(R)-2-(2-morfolin-4-il-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,N - ((3R) oxolan-3-yl) {5 - [(5-fluoro-2-oxo (1 H -benzo [d] azolin-3-ylidene)) methyl] -2,4-dimethylpyrrol-3-yl } Carboxamide, [(R) -2- (2-morpholin-4-yl-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2 -dihydro-indole- (3Z) - ylidenemethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic, [(S)-1-(2-metoxi-etil)-2-oxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,[(S) -1- (2-Methoxy-ethyl) -2-oxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxyNico, ((S)-2-oxo-1-piridin-4-ilmetil-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1H-pirrol-3-carboxNico,((S) -2-Oxo-1-pyridin-4-ylmethyl-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico, [(R)-3-oxo-2-(tetrahidro-piran-4-ilmetil)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-[(R) -3-Oxo-2- (tetrahydro-pyran-4-ylmethyl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - 55 1010 15fifteen 20twenty 2525 3030 3535 4040 45Four. Five 50fifty 5555 6060 6565 ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico, [(S)-1-(2-metoxi-etil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[(S) -1- (2-Methoxy-ethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H -pyrrole-3-carboxyNico, [1-(2-metoxi-etil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H- pirrol-3-carbox^lico,[1- (2-Methoxy-ethyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2.4 -dimethyl-1H-pyrrole-3-carboxylic acid, [1-(2-dimetilamino-acetil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[1- (2-Dimethylamino-acetyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4 - dimethyl-1 H-pyrrole-3-carboxynic, [(S)-1-(2-dimetilamino-acetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(S) -1- (2-Dimethylamino-acetyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid, [1-(2-hidroxi-etil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H- pirrol-3-carbox^lico,[1- (2-Hydroxy-ethyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2.4 -dimethyl-1H-pyrrole-3-carboxylic acid, [(S)-1-(2-hidroxi-etil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-mdol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[(S) -1- (2-Hydroxy-ethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-mdol- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H -pyrrole-3-carboxyNico, (6'-metil-3,4,5,6-tetrahidro-2H-[1,3']bipiridinil-4-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,5- (5-Fluoro-2-oxo-1,2-dihydro) acid (6'-methyl-3,4,5,6-tetrahydro-2H- [1,3 '] bipyridinyl-4-yl) -amide -indole- (3Z) -lidenemethyl] -2,4-dimethyl-1H-pyrrole-3-carboxyNico, [(S)-1-(6-metil-piridin-3-il)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(S) -1- (6-methyl-pyridin-3-yl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxyNico, [(S)-2-oxo-1-(tetrahidro-piran-4-ilmetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(S) -2-Oxo-1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic, [1-(2-metanosulfonil-etil)-piperidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[1- (2-Methanesulfonyl-ethyl) -piperidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4 - dimethyl-1 H-pyrrole-3-carboxynic, [(S)-1-(2-metanosulfonil-etil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(S) -1- (2-Methanesulfonyl-ethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4- dimethyl-1 H-pyrrole-3-carboxyNico, [(R)-2-(2-metanosulfonil-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(R) -2- (2-Methanesulfonyl-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxNico, [(S)-2-(2-metoxi-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(S) -2- (2-Methoxy-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ilidenmethyl] - 2.4- dimetil-1 H-pirroi-3-carboxilico,2.4-dimethyl-1 H-pyrroi-3-carboxylic acid, [(R)-2-(2-etoxi-etil)-3-oxo-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[(R) -2- (2-Ethoxy-ethyl) -3-oxo-isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z ) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3-carboxyNico, [(S)-1-(2-metoxi-etil)-2,5-dioxo-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-[(S) -1- (2-Methoxy-ethyl) -2,5-dioxo-pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ilidenmethyl] - 2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid, [(R)-3-oxo-2-(tetrahidro-furan-3-ilmetil)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1H-pirrol-3-carboxNico,[(R) -3-Oxo-2- (tetrahydro-furan-3-ylmethyl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimethyl-1H-pyrrole-3-carboxynic, [(R)-3-oxo-2-(tetrahidro-furan-2-ilmetil)-isoxazolidin-4-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetiMH-pirrol-3-carboxNico,[(R) -3-Oxo-2- (tetrahydro-furan-2-ylmethyl) -isoxazolidin-4-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) - ilidenmethyl] -2,4-dimetiMH-pyrrole-3-carboxyNico, [(S)-2,5-dioxo-1-(tetrahidro-piran-4-ilmetil)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetiMH-pirrol-3-carboxNico,[(S) -2,5-dioxo-1- (tetrahydro-pyran-4-ylmethyl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro- indole- (3Z) - ylidenemethyl] -2,4-dimetiMH-pyrrole-3-carboxNico, [(S)-2,5-dioxo-1-(tetrahidro-piran-4-il)-pirrolidin-3-il]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)- ilidenmetil]-2,4-dimetil-1 H-pirrol-3-carboxNico, y[(S) -2,5-dioxo-1- (tetrahydro-pyran-4-yl) -pyrrolidin-3-yl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro- indole- (3Z) - ylidenemethyl] -2,4-dimethyl-1 H -pyrrole-3-carboxynic, and ((S)-1-dimetilcarbamoil-2-oxo-pirrolidin-3-il)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-((S) -1-Dimethylcarbamoyl-2-oxo-pyrrolidin-3-yl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 2.4- dimetil-1 H-pirrol-3-carboxflico.2.4-dimethyl-1 H-pyrrole-3-carboxylic. 6. El compuesto de la reivindicacion 1 que se selecciona entre:6. The compound of claim 1 selected from: (4-hidroxi-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3- carboxNico,(4-Hydroxy-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1 H-pyrrole-3- carboxNico, (4-amino-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3- carboxNico,(4-Amino-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1 H-pyrrole-3- carboxNico, (4-oxo-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol-3- carboxilico,(4-Oxo-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3- carboxylic, ((1S,2S)-2-hidroxi-ciclopentil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1H- pirrol-3-carbox^lico,((1S, 2S) -2-hydroxy-cyclopentyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenemethyl] -2,4-dimethyl-1H - pyrrole-3-carboxylic acid, ((1 S,2R)-2-hidroxi-ciclopentil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H- pirrol-3-carbox^lico,((1 S, 2R) -2-Hydroxy-cyclopentyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H- pyrrole-3-carboxylic acid, (4-acetilamino-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H-pirrol- 3-carboxNico,(4-Acetylamino-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-pyrrole-3- carboxNico, (4-metanosulfonilamino-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,(4-Methanesulfonylamino-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H -pyrrole-3- carboxNico, ((1 S,2S)-2-hidroxi-ciclohexil)-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil-1 H- pirrol-3-carbox^lico,((1 S, 2S) -2-Hydroxy-cyclohexyl) -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H- pyrrole-3-carboxylic acid, [4-(morfolina-4-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxNico,[4- (Morpholine-4-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H-Pyrrole-3-CarboxNico, [4-(pirrolidina-1-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4- dimetil-1 H-pirrol-3-carboxNico,[4- (Pyrrolidine-1-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl-1 H-Pyrrole-3-CarboxNico, [4-(aziridina-1-carbonil)-ciclohexil]-amida del acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-2,4-dimetil- 1 H-pirrol-3-carboxilico,[4- (Aziridine-1-carbonyl) -cyclohexyl] -amide of the acid 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] -2,4-dimethyl- 1 H-pyrrole-3-carboxylic acid, 55 1010 15fifteen 20twenty 2525 3030 [(1R,3S)-3-(pirrolidina-1-carbonil)-ciclopentil]-amida del[(1R, 3S) -3- (pyrrolidine-1-carbonyl) -cyclopentyl] -amide 2.4- dimetil-l H-pirrol-3-carboxilico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid, [(1 R,3S)-3-(morfolina-4-carbonil)-ciclopentil]-amida del[(1 R, 3S) -3- (morpholine-4-carbonyl) -cyclopentyl] -amide 2.4- dimetil-1 H-pirrol-3-carboxilico, [(1R,3S)-3-(aziridina-1-carbonil)-ciclopentil]-amida del2,4-dimethyl-1 H-pyrrole-3-carboxylic, [(1R, 3S) -3- (aziridine-1-carbonyl) -cyclopentyl] -amide 2.4- dimetil-1 H-pirrol-3-carbox^lico, [(1R,2S)-2-(pirrolidina-1-carbonil)-ciclopentil]-amida del2,4-dimethyl-1 H-pyrrole-3-carboxylic acid, [(1R, 2S) -2- (pyrrolidine-1-carbonyl) -cyclopentyl] -amide 2.4- dimetil-1 H-pirrol-3-carbox^lico,2.4-dimethyl-1 H-pyrrole-3-carboxylic acid, [(1 R,2S)-2-(morfolina-4-carbonil)-ciclopentil]-amida del[(1 R, 2S) -2- (morpholine-4-carbonyl) -cyclopentyl] -amide 2.4- dimetil-1 H-pirrol-3-carbox^lico, y [(1R,2S)-2-(aziridina-1-carbonil)-ciclopentil]-amida del2,4-dimethyl-1 H-pyrrole-3-carboxylic acid, and [(1R, 2S) -2- (aziridine-1-carbonyl) -cyclopentyl] -amide 2.4- dimetil-1 H-pirrol-3-carbox^lico.2.4-dimethyl-1 H-pyrrole-3-carboxylic. acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]- acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]- acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]- acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]- acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]- acido 5-[5-fluoro-2-oxo-1,2-dihidro-indol-(3Z)-ilidenmetil]-5- [5-Fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) acid -ilidenmethyl] - 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 5- [5-fluoro-2-oxo-1,2-dihydro-indole acid - (3Z) -ylidenmethyl] - 5- [5-fluoro-2-oxo-1,2-dihydro-indole- (3Z) -ylidenmethyl] - 5- [5-fluoro-2-oxo-1,2 acid -dihydro-indole- (3Z) -ylidenmethyl] - 7. Un compuesto de una cualquiera de las reivindicaciones 1 a 6 o sal, solvato o hidrato farmaceuticos del mismo, para su uso en un metodo de tratamiento de una enfermedad o un sintoma de enfermedad.7. A compound of any one of claims 1 to 6 or pharmaceutical salt, solvate or hydrate thereof, for use in a method of treating a disease or a symptom of disease. 8. El compuesto para su uso de acuerdo con la reivindicacion 7, en donde la enfermedad o el sintoma de enfermedad son modulados por una enzima quinasa.8. The compound for use according to claim 7, wherein the disease or disease symptom is modulated by an enzyme kinase. 9. El compuesto para su uso de acuerdo con la reivindicacion 8, en donde la enfermedad o el sintoma de enfermedad son modulados por una cualquiera o cualquier combinacion de las quinasas seleccionadas entre VEGFR, PDEGFR, KIT, Flt-1, Flt-3, Flt-4 y RET.9. The compound for use according to claim 8, wherein the disease or disease symptom is modulated by any one or any combination of the kinases selected from VEGFR, PDEGFR, KIT, Flt-1, Flt-3, Flt-4 and RET. 10. El compuesto para su uso de acuerdo con la reivindicacion 8, en donde la enfermedad o el sintoma de enfermedad son cancer, tumor o un trastorno proliferativo.10. The compound for use according to claim 8, wherein the disease or disease symptom is cancer, tumor or a proliferative disorder. 11. El compuesto para su uso de acuerdo con la reivindicacion 10, en donde el compuesto inhibe selectivamente una diana quinasa preferentemente sobre la inhibicion de AMPK.11. The compound for use according to claim 10, wherein the compound selectively inhibits a kinase target preferably on AMPK inhibition. 12. Uso de un compuesto de una cualquiera de las reivindicaciones 1 a 6 en la fabricacion de un medicamento para tratar una enfermedad o un sintoma de enfermedad en un sujeto que lo necesite.12. Use of a compound of any one of claims 1 to 6 in the manufacture of a medicament for treating a disease or a symptom of disease in a subject in need thereof. 13. Una composicion que comprende un compuesto de formula I, o sal farmaceuticamente aceptable del mismo, de acuerdo con cualquiera de las reivindicaciones 1-6 y un vehiculo farmaceuticamente aceptable.13. A composition comprising a compound of formula I, or pharmaceutically acceptable salt thereof, according to any of claims 1-6 and a pharmaceutically acceptable carrier.
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